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The mechanistic basis of the congenital HDs has not yet been established for each syndrome. Findings of laterality defects should reflect disruption of LRO function, whereas isolated congenital HDs might result from abnormalities of cilia within the heart.
Cardiomyopathy is identified in Alstrom syndrome. The prevalence varies by syndrome subtype, but all syndromes are quite rare, with estimates ranging from to There are examples of founder effects, with the incidence of Meckel-Gruber as high as in some populations Finnish.
As seen in Table 7 , several of the disorders have allelic overlap. For example, Joubert syndrome and Meckel-Gruber syndrome share many of the same genetic causes.
How the same allele causes disparate phenotypes for many of the ciliopathies is not fully apparent. For the multisystem disorders, specific organ involvement or severity can correlate with the particular gene involved.
For example, in a patient with Joubert syndrome, pathogenic variants in NPHP1 , a gene that can also cause nephronophthisis, are more likely to be found in association with renal involvement.
Modifier alleles and digenic inheritance have been described, and these presumably affect phenotypic presentation.
In some cases, the variant type eg, loss of function versus missense will dictate presentation.
Genotype-phenotype correlations have not been described for cardiac presentations. Studies of the mouse model predict that ciliary defects will be identified that cause recessively inherited isolated congenital HD in the absence of a syndromic ciliopathy or PCD, and recent studies show an over-representation of rare, predicted damaging variants in recessive genes in patients with isolated congenital HD versus control subjects.
Recent work on large cohorts of patients with severe mitral valve prolapse identified that mutations affecting DCHS1 are linked to congenital mitral valve defects, and DCHS1 localizes to the base of the ciliary apparatus.
In the future, genomic analyses of large cohorts of congenital HD will likely yield additional cilia genes with a role in congenital HD and begin to establish more focused genotype-phenotype correlations.
Clinical genetic testing is directed on the basis of the differential established through medical history, including family history, and physical examination.
All patients with heterotaxy should have CMA because of associations with chromosome abnormalities and pathogenic CNVs. In addition, strong consideration should be given to ZIC3 testing, particularly in males with heterotaxy.
Recurrence risk estimates are substantially impacted by test results. Although additional studies are necessary to further establish the prevalence of PCD in patients with heterotaxy, consideration should be given to evaluation for PCD, because respiratory and pulmonary management could be optimized to improve the higher than expected surgical morbidity and mortality in this patient group.
Concern for syndromic ciliopathies should prompt molecular testing for these disorders via ciliopathy panels or exome sequencing.
One of the challenging aspects of caring for patients requiring surgical repair of congenital HD is the variation in postoperative outcomes even for patients with anatomically and physiologically identical congenital HD.
Respiratory complications are one of the most important modulators of postoperative outcome that can be influenced by genetic pathogenesis of the congenital HD.
If patients at increased risk for respiratory and other complications can be identified preoperatively, it might be possible to modify their care and improve clinical outcomes.
Pathological variants in ciliary genes are known to cause heterotaxy, some types of nonheterotaxy congenital HD, , and PCD.
With this in mind, it is not surprising that patients with congenital HD, heterotaxy, and associated airway ciliary dysfunction have a higher rate of respiratory complication postoperatively than similar patients without airway ciliary dysfunction.
As discussed earlier, numerous genes have been implicated in the pathogenesis of congenital HD when it occurs in the setting of a genetic syndrome, but the identification of the genetic contributors of nonsyndromic congenital HD has proved to be more challenging.
Although initial insights were based on studies of large, multigenerational kindreds in which multiple family members were affected with a cardiac malformation, these families are relatively uncommon, and the congenital HD is often less severe.
Establishing disease causality, especially of a specific variant, remains a challenge. These genes mostly encode transcription factors, signaling molecules, or structural proteins important in cardiac development, structure, and function.
Detailed information about the associated cardiac phenotypes and references to supporting studies are reviewed in Anderson et al and Fahed et al and are provided in Table 8.
Many of the congenital HD genes identified to date can be assigned to one of the following functional categories.
Initial insights into the genetic pathogenesis of non-syndromic congenital HD were based on the discovery of disease-causing sequence variants in critical cardiac transcription factors identified as important for normal heart development in multiple animal model systems.
A similar approach identified heterozygous mutations in GATA4 , a gene encoding another important cardiac transcription factor, in familial congenital HD.
Evidence supporting these genetic associations has come from analysis of mice haploinsufficient for Gata4 or harboring disease-causing Gata4 mutations.
These mouse models have replicated human disease phenotypes. Another important transcription factor family linked to congenital HD is the Tbox family.
Other cardiac transcription factors implicated in congenital HD pathogenesis are listed in Table 8. Garg et al reported a multigeneration family with autosomal dominant cardiovascular disease in which 9 members had aortic valve disease, primarily BAV, but also 1 member with tetralogy of Fallot.
Given the large number of genes that contribute to congenital HD, NGS is being increasingly used in both research and clinical settings in congenital HD patients.
In one of the earliest studies led by the Pediatric Cardiac Genomics Consortium that used WES in severe congenital HD cases parent-offspring trios , congenital HD cases showed a significant excess of proteinaltering de novo sequence variants in genes expressed in the developing heart, with particular enrichment of histone-modifying genes that regulate expression of key developmental genes.
The same group performed exome sequencing of congenital HD parent-offspring trios and identified an excess of protein-damaging de novo variants in genes highly expressed in the developing heart and brain.
These findings revealed shared genetic contributions to congenital HD, neurodevelopment, and extracardiac anomalies.
A large international study using WES of probands found a significant enrichment of de novo protein-truncating variants but not inherited protein-truncating variants in known congenital HD genes in syndromic congenital HD.
Conversely, in nonsyndromic congenital HD, there was a significant enrichment of protein-truncating variants inherited from unaffected parents in congenital HD genes.
This study underscored the distinct genetic architectures of syndromic versus nonsyndromic congenital HD.
Finally, a recent study using mouse forward genetics identified sequence variants in novel genes not previously associated with congenital HD, Sap and Pcdha9 , as being digenic causes of HLHS.
Sap mediated left ventricular hypoplasia, whereas Pcdha9 increased penetrance of aortic valve abnormalities. There are several hundred genes that either cause or contribute to congenital HD.
Sequence variants in congenital HD genes can cause both sporadic and inherited congenital HD. Sequence variants in congenital HD genes can cause both syndromic and nonsyndromic congenital HD, with strong association of de novo variants with syndromic CHD and of inherited variants with nonsyndromic congenital HD.
There is phenotypic heterogeneity, with sequence variants in the same genes often associated with different cardiac phenotypes, not only between families but also within families.
Family studies often show incomplete segregation even in familial congenital HD, with could be attributable in part to incomplete penetrance but could also be related to oligogenic origins of congenital HD.
The above findings have clinical implications. Although several laboratories offer congenital HD gene panels of various sizes for clinical testing, the relatively large numbers of genes involved and the role of novel and ultra-rare variants in causing rare disorders coupled with the oligogenic origins of some of the more complex congenital HDs suggest that a genome-wide search for congenital HD—associated variants might be cost-effective in the future as the accuracy of variant interpretation improves.
Experience, challenges, and cost-effectiveness of clinical exome sequencing have been reported recently. Widespread exome and genome sequencing of congenital HD patients is uncovering an ever-increasing number of candidate disease genes and disease-causing variants.
Several in vitro and in vivo model systems are available, each with its own strengths and weaknesses.
Recently, in vitro strategies have been developed in cell and tissue engineered models that complement the animal models and facilitate mechanistic studies.
These key features have made the murine system the most widely studied animal model of cardiovascular development.
The mouse genome can be modified by many techniques. These can be grouped into methods that randomly insert DNA sequences into the genome transgenesis and those that modify an endogenous locus targeted mutagenesis.
Transgenesis, performed by introduction of foreign DNA using a targeting vector into a fertilized oocyte, is most commonly used to direct expression of a gene in an altered form or at an ectopic time, location, or level.
The targeting vector used to modify the endogenous locus can be engineered to inactivate the gene knockout , to introduce recombinase sites into the gene so that it can be conditionally inactivated by a second recombinase allele eg, flank gene with loxP sites [floxed] that can be excised at a specific time in a specific tissue by Cre recombinase , or to modify the endogenous gene knockin.
These techniques for modifying the mouse genome have been used to study cardiovascular development and disease in a number of ways. The opposite loss-of-function strategy is achieved by constitutive gene knockout or by excising an essential portion of a floxed gene of interest using Cre recombinase, expressed from a transgene or knocked into a second locus so that it is expressed in a known spatiotemporal domain.
Gene knockout approaches have traditionally focused on coding regions. However, this strategy will also be useful to test the functional importance of conserved transcriptional regulatory elements that have been linked to congenital HD causation using high-throughput mapping technologies.
Because reporter activation involves modification of the genome, it is transmitted to all of the progeny of the Cre-expressing cells.
Lineage tracing has been critical to deduce the developmental events that generate the heart, including the contributions of the second heart field, which adds cells onto the arterial and venous ends of the linear heart tube to form parts of the atria and most of the right ventricle and outflow tract, as well as the contribution of the dorsal mesenchymal protrusion to form portions of the atrioventricular septae at the crux of the heart.
Because of practical considerations, congenital HD gene defects are often modeled in mice as homozygous gene knockouts, whereas most congenital HD mutations are heterozygous point or truncating mutations.
Biologically, gene dosage and redundancy are important factors that influence the expression of mutations, and these parameters often vary between species.
For instance, haploinsufficiency of TBX1 in 22q11 deletion syndromes is an important contributor to congenital HD ; however, Tbx1 haploinsufficiency is well tolerated in mouse models, and a more severe reduction of Tbx1 dosage is required to produce cardiac defects.
As a result of these technical and biological factors, mouse models often yield important principles and genetic pathways responsible for congenital HDs, but genotype-phenotype relationships can differ between the mouse and the human.
As noted above, cost and time are important considerations when developing mouse models of congenital HD. Creating a new mouse allele and characterizing it can take 6 to 12 months, and in models that require combining several different alleles, breeding mice to obtain the required genotype can be a critical practical bottleneck.
Acquiring the correct mouse alleles for an experiment can also be time consuming and expensive. In some cases, these practical limitations can be circumvented through in vivo gene transfer and somatic mutagenesis.
Although it is possible to deliver adeno-associated virus to late-stage mouse embryos, unfortunately at the present time, adeno-associated virus transduction of mid-gestation mouse embryos and noncardiomyocytes such as endothelial cells and valve cells is inefficient and thus not applicable to many heart development studies.
The limitations of the mouse model have led to the use of alternative vertebrate models to study cardiovascular development.
The zebrafish has become an attractive experimental model; the genes and signaling pathways involved in human cardiac development and responsible for human congenital cardiac defects are highly conserved in the zebrafish, and the zebrafish offers some important advantages for developmental studies.
A key advantage of the zebrafish system over mice is that embryos are transparent and develop outside the body of the mother ex utero , which permits the developing cardiovascular system to be imaged throughout the developmental process.
Rapid screening of candidate congenital HD disease genes for essential functions in heart development can be performed with antisense strategies to diminish expression of specific genes beginning very early in development.
Unfortunately, this approach, which uses stable antisense RNA constructs called morpholinos, can yield nonspecific morphological defects that can obscure gene function, requiring careful confirmation of observed phenotypes.
One important consideration when performing targeted genetic modifications is that the zebrafish underwent a genome duplication event during evolution after divergence from its common ancestor with mammals.
One popular approach to verifying that newly identified variants are indeed pathogenic is to determine whether a full-length expression construct of the wild-type and mutated versions of the gene is capable of rescuing the phenotype of zebrafish that lack a functional copy of the gene.
This can be readily accomplished by directly injecting capped mRNA into 2- to 4-cell-stage embryos, leading to widespread expression of wild-type or mutant transcripts of genes known or suspected to be involved in cardiac development.
Furthermore, expression of a mutant form of the gene in a wild-type embryo can help rapidly validate gain-of-function variants that have a dominant-negative effect on heart development.
The ex utero development of zebrafish embryos also permits interventions that are not possible in mouse.
Addition of agents to the aquatic environment of the embryo can be used to examine the teratogenic effects of environmental toxins or interrogate the developmental contributions of specific signaling pathways.
Each of these interventions has helped to examine specific aspects of cardiac development in a manner that would not be possible in a higher vertebrate model in which the embryo develops in utero.
A major limitation of the zebrafish model is that the zebrafish has a 2-chambered heart 1 atrium and 1 ventricle , which makes it unsuitable for examination of the developmental process of septation.
However, genetic mutations that lead to septal defects in humans cause detectable cardiac phenotypes in zebrafish embryos, which means the zebrafish is still a useful screening tool to examine the pathogenicity of mutations that are suspected of causing septation defects in humans.
Another vertebrate model system that has the benefit of developing ex utero, which enables the observation and manipulation of developmental processes, is the chick embryo.
It has the additional benefit of having a 4-chambered heart that is much more similar to the human heart and can be used to study septation and other, more complex processes in cardiac morphogenesis.
As with the zebrafish model, delivery of gene expression or antisense RNA constructs can be used to manipulate gene expression, allowing examination of gene functions and the developmental pathways.
A strength of the chick model system is the ability to examine the effects of embryo manipulation on cardiac development.
For instance, surgical interventions such as left atrial or vitelline vein ligation alter intracardiac flow patterns and result in abnormalities of cardiac morphogenesis, , and ablation of specific developmental fields, such as the cardiac neural crest, allows determination of the contribution of those domains to the cardiac development.
The combination of mechanical or pharmacological intervention with modification of gene expression can facilitate characterization of the effects of gene-environment interactions on heart development and is a particular strength of the chick embryo model system.
Although each animal model has its strengths in studying cardiac development and the pathological processes that cause human congenital cardiac defects, many lack the resolution to study the cellular interactions that are the foundation of organ development, and none can fully recapitulate the complex and unique genetic environment of a patient with congenital HD.
Therefore, in vitro model systems, including those with the ability to directly examine the development of human patient—derived cells, have been developed to better understand cell-level interactions that guide heart development.
Although mammalian heart development cannot be fully recapitulated ex utero in culture systems, culture systems have been essential for mechanistic studies of cardiovascular development.
Mammalian embryos remain viable and continue to develop for hours to days in culture environments, which permits key questions on lineage, mechanics, and molecular signaling to be studied.
Primary cell culture models have also been essential for studies of cardiovascular development. Stem cell differentiation into cardiomyocytes has become a powerful method to study cardiogenesis and early heart development.
Cardiac progenitor cells are scarce in developing embryos, which makes studies that require thousands to millions of cells difficult.
In contrast, millions of these cells can be efficiently generated in stem cell differentiation cultures. This has allowed key regulatory steps of cardiogenesis and early heart development to be carefully dissected.
These technologies include 1 development of efficient methods for human stem cell differentiation; 2 reprogramming of somatic cells to induced pluripotent stem cells, which allows for the creation of patient-specific disease models; 3 facile genome editing, which permits rapid genetic manipulation of stem cells; and 4 development of bioengineered systems to build engineered heart tissues and assay them for relevant physiological parameters.
This confluence of technical advances has allowed the impact of congenital HD mutations on cardiomyocyte gene expression, cardiac differentiation, and myocardial function to be evaluated in patient-specific genetic backgrounds, yielding new insights in disease pathogenesis.
Among these are developing in vitro, stem cell—based models of cardiac morphogenesis; enhancing directed differentiation of stem cells to the full gamut of cardiac cell types; and improving the maturation of in vitro differentiated cardiomyocytes.
Although beyond the scope of this scientific statement, it is important to mention the growing role of in silico modeling of genetic variants to determine the potential effects of the variant on protein structure and function.
Early algorithms relied almost entirely on the effect of the amino acid alteration on protein structure to determine whether the mutation was likely to be pathogenic.
More recently, algorithms have incorporated degree of evolutionary conservation, population frequency, and, in some cases, more advanced functional modeling to determine potential pathogenicity of a novel genetic variant.
Increasingly, advances in the understanding of the functions of and pathophysiological mechanisms associated with specific disease-causing variants gained from the above in vivo and in vitro models will allow more refined disease gene—specific mathematical modeling to assess potential pathogenicity of specific genetic variants, better characterization of disease mechanisms, and identification of structural domains suitable for pharmacological targeting.
In summary, technical advances and our expanding knowledge base have fueled dramatic advances in the in vitro and in vivo modeling of cardiac development.
Continued expansion of these modeling capabilities will allow the rapid screening and adjudication of potential congenital HD disease genes and pathogenic variants and the examination of potential therapeutic approaches.
As noted above, genetic testing for congenital HD has increased over the past 10 years 94 , and is particularly helpful in diagnosing syndromes responsible for congenital HD and related noncardiac phenotypes that might require clinical management.
In addition, there is increasing evidence that certain types of genetic variations that cause congenital HD also affect clinical outcomes such as cognition, behavior, and motor skills collectively termed neurodevelopmental performance.
Despite these potential benefits, uncertainty about the clinical significance of many genetic variants and the complexity of conveying this information present challenges.
Sequencing has uncovered many more genetic associations with congenital HD, 94 but variant interpretation is imprecise, and the interplay between genetic and environmental factors that contribute to congenital HD continues to be elusive.
With NGS, there is also the possibility that genetic variants associated with congenital HD might be discovered incidentally when testing for an unrelated phenotype, or that clinically significant incidental findings unrelated to congenital HD could be detected when testing for congenital HD.
In , the American College of Medical Genetics and Genomics ACMG recommended that certain clinically actionable secondary findings, including a number of cardiac-related variants, such as Ehlers-Danlos syndrome, familial thoracic aortic aneurysms, Marfan syndrome, and HCM, ought to be offered to all patients undergoing clinical WES or whole genome sequencing.
In these situations, referral to a cardiovascular geneticist is advisable. On the flipside, when performing a genomic test for congenital HD, patients ought to be informed about the potential to discover incidental findings unrelated to congenital HD and should be given an opportunity to opt out of those results.
Additional challenges are raised when performing genetic testing in children with congenital HD. For many years, there has been a general consensus that children should only receive genetic testing that offers the potential for direct clinical benefit during childhood.
Targeted genetic testing is only plausible when there is a known family history of a mendelian condition that puts the child at risk for disease.
In this situation, the affected family member already knows that he or she has, or is at risk for, the targeted genetic variant.
In the context of genomic sequencing, however, a variant associated with an adult-onset condition that is discovered in a child could benefit parents or other family members, who would not otherwise know they are at risk.
Pretest genetic counseling for congenital HD should address the potential risks and benefits of testing, including the psychological and social impact of receiving a positive test result.
Recent studies suggest that neither adults nor children , experience significantly increased anxiety or distress after learning of their genetic status.
However, the potential psychosocial impact of genetic testing can be greater when test results offer little therapeutic value and could include alterations of self-image and disruption in family relationships, including increased perceptions of child vulnerability that negatively impact development.
For example, patients and families might experience relief from the reduction of uncertainty when a genetic cause is discovered.
Even when the clinical and psychological benefits outweigh the risks, however, uptake of genetic testing for congenital HD can be limited if patients are concerned about the misuse of genetic information for discriminatory purposes.
Although there have been very few documented cases of genetic discrimination, even before the passage of GINA, current regulatory uncertainty has the potential to negatively impact patients and families.
A trustworthy system that provides robust protection against genetic discrimination is needed if we are to reap the benefits of advances in genetic testing for congenital HD that have been realized over the past 10 years.
The National Society of Genetic Counselors describes genetic counseling as the process of helping people understand and adapt to medical, psychological, and familial implications of genetic contributions to disease.
This process integrates 1 interpretation of family and medical histories to assess the probability of disease occurrence or reoccurrence; 2 education about inheritance, testing, management, prevention, resources, and research; and 3 counseling to promote informed choices and adaptation to the risk or condition.
In the United States and Canada, this terminal degree leads to certification through the American Board of Genetic Counseling after the individual passes a national certification examination.
As of May , 20 states issue and require licensure for genetic counselors to practice, and 3 states have licensure laws in progress.
As the need for cardiovascular genetic counseling is increasingly recognized, genetic counseling training programs are developing curricula and clinical rotations to meet this growing need.
Genetic counselors skilled in cardiovascular genetics have become an invaluable clinical asset, helping not only to provide accurate recurrence risks but also to obtain family and medical histories, facilitate appropriate genetic testing, interpret test results, make necessary subspecialty referrals, and provide attendant psychosocial support for patients and their families.
Physicians with subspecialty training in medical genetics are trained in dysmorphology, metabolism, monogenic conditions, genomics, and diagnostic testing and are able to generate a differential, determine a diagnostic evaluation approach, and provide specific management and treatment recommendations for patient care.
In addition, geneticists can evaluate family members for other syndromic features and facilitate appropriate genetic testing or referrals.
Studies have shown that genetics consultation increases the diagnostic rate of genetic syndromes in infants in the cardiac intensive care unit, as well as in older children with congenital HD seen for follow-up in a cardiac neurodevelopmental clinic.
Dysmorphology evaluation is challenging in infants, and expanded testing identifies abnormalities missed even by trained dysmorphologists.
Algorithms have been proposed based on expert recommendation; further evidence-based investigation is necessary.
Genetic counseling services are valued by families. Telemedicine services are emerging in response to this need. Many centers are developing triage algorithms and testing new counseling models.
Genetic assistants are being piloted to augment genetic counselor functions and expand capacity.
Continued integration of genetic evaluation and genetic counseling are important components for improving utilization of increasingly comprehensive and affordable genetic services.
Furthermore, it is becoming increasingly important that practitioners in the care of patients with congenital HD develop a level of comfort and expertise in genetic concepts and terminology.
With that in mind, the American Heart Association recently published a scientific statement on enhancing provider literacy in cardiovascular genetics.
The distinction between syndromic and nonsyndromic, or isolated, congenital HD can be subtle. Technological advancements in genetic testing have increased the diagnostic yield.
Studies of patients with congenital HD do not always apply the same criteria to distinguish syndromic from nonsyndromic cases, and the age of patient evaluation influences assessment.
In general, recurrence estimates are more precise for syndromic than for isolated congenital HDs, because genes and associated inheritance patterns for many congenital HD—associated monogenic conditions are already known.
Importantly, not all patients with a particular syndrome will present with structural heart defects, and the proportion who do can vary considerably depending on the specific diagnosis.
The likelihood of affected individuals reaching reproductive age or having children reproductive fitness is related to the new mutation rate that is a common cause of syndromic congenital HDs.
As a result, some genetic syndromes that are highly penetrant for congenital HD contribute less to the congenital HD burden in the next generation than is the case for patients with isolated congenital HD or less severe lesions.
Epidemiological studies can underestimate the number of familial cases because of the high rate of miscarriages of fetuses with congenital HDs and reproductive decisions to limit future pregnancies in families with a child with a congenital HD.
As genetic testing technologies have evolved to offer higher resolution and higher diagnostic yields than those provided by conventional chromosomal analyses, CNVs have emerged as important causes of both syndromic and nonsyndromic congenital HDs.
Moreover, an increasing recognition of contributing environmental and epigenetic factors has revealed a previously unanticipated breadth to congenital HD pathogenesis.
The study of groups of embryologically related cardiac malformations has identified subclasses of congenital HDs with strong familial clustering in first-degree relatives, ranging from 3-fold to fold compared with the prevalence in the population.
In the case of left ventricular outflow tract obstructive defect, it also has implications for cardiac screening in family members.
Not all families show evidence of similar types of congenital HDs, and familial clustering of discordant congenital HDs has also been documented, which suggests that common genetic pathways might underlie a spectrum of CHDs reviewed in Landis and Ware Because congenital HDs are so common, the majority of cases occur in individuals without a family history despite high heritability.
Although the incidence of congenital HDs appears to be similar in most populations, there are some specific types of congenital HD that show important differences.
Data from references — except where otherwise noted. Merged cells indicate recurrence when 1 parent is affected, irrespective of sex, and are used in the absence of sex-stratified risks.
Reprinted from Cowan and Ware 13 with permission from Elsevier. Preimplantation genetic diagnosis is an assisted reproductive technology that allows screening for a genetic condition after in vitro fertilization and before implantation.
Preimplantation genetic diagnosis can be used in couples at risk for passing on a genetic condition, including carriers of X-linked disorders, single-gene disorders, and chromosomal disorders.
Until , noninvasive prenatal screening consisted mainly of measurements of maternal serum analytes and ultrasonography. In , fcfDNA screening also referred to as noninvasive prenatal testing, NIPT, or noninvasive prenatal diagnostic screening became clinically available.
The ACMG recommends informing all pregnant women that fcfDNA screening is the most sensitive noninvasive screening for aneuploidies such as trisomy 21, trisomy 18, and trisomy One review analysis, published in , found the pooled sensitivities for fcfDNA screening to be Screening for other autosomal aneuploidies besides trisomy 21, 18, and 13 is not yet recommended.
The ACMG guidelines recommend offering fcfDNA screening to high-risk families those with advanced maternal age or fetal anomalies on ultrasound , as well as lower-risk families.
Clinically significant CNVs are rare in the population, and the positive predictive value is much lower than for whole chromosome aneuploidy.
If fcfDNA screening should identify a CNV or sex chromosome abnormality, then invasive diagnostic testing by chorionic villus sampling or amniocentesis is recommended by the ACMG guidelines to confirm the diagnosis.
If fetal ultrasounds or echocardiograms are abnormal, the American College of Obstetricians and Gynecologists and the Society of Maternal Fetal Medicine recommend prenatal CMA if invasive prenatal diagnosis is performed.
Informed consent and comprehensive pretest and posttest genetic counseling are necessary. Fetal echocardiography is now widely used to detect, characterize, and help manage congenital cardiac malformations.
Indications for performing a fetal echocardiogram have been formulated and were described in a recent American Heart Association scientific statement.
As might be expected, the strength of Classification of Recommendation is reduced in more distantly related family members: with congenital HD in a second-degree family member, a fetal echocardiogram may be considered Class IIb ; with the nearest relative s with congenital HD being a third-degree or more distant family member s , a fetal echocardiogram is not recommended Class III.
Similarly, fetal echocardiograms should be performed in pregnancies in which there is a heritable condition in a first-degree family member that is associated with a risk of heart defects such as NS even if the affected relative does not have a heart defect.
However, for heritable cardiac conditions with a later onset of manifestation such as HCM, Marfan syndrome, or Loeys-Dietz syndrome , fetal echocardiography may not be necessary if screening obstetrical ultrasound does not demonstrate any abnormalities.
Demonstration of noncardiac abnormalities suggestive of a potential genetic syndrome, teratogen, or malformation sequence is also an important indication to perform a fetal echocardiogram.
Our understanding of the role of genetics in the pathogenesis of congenital HD has advanced at a rapid pace over the past 10 to 15 years.
The availability of new molecular techniques has facilitated gene discoveries that have changed the medical and cardiological care of many individuals with congenital HD.
CNV detection and NGS gene panels are now in widespread use by geneticists, genetic counselors, and cardiologists for accurate diagnosis of congenital HD patients.
Cardiovascular genetics clinics are now available in many major medical centers in the United States. Accurate diagnosis of congenital HD pathogenesis is allowing for determination of familial recurrence risks, providing reproductive options, identifying extracardiac manifestations of the genetic diagnosis that could affect clinical care, and improving long-term medical decisions in the care of congenital HD.
Additionally, WES is now used in many centers for those congenital HD patients suspected of having a genetic disorder when no pathogenetic diagnosis was obtained by other molecular testing.
The authors thank Patricia Buenzle, University of Minnesota, for her assistance in the preparation of the manuscript.
This table represents the relationships of writing group members that may be perceived as actual or reasonably perceived conflicts of interest as reported on the Disclosure Questionnaire, which all members of the writing group are required to complete and submit.
This table represents the relationships of reviewers that may be perceived as actual or reasonably perceived conflicts of interest as reported on the Disclosure Questionnaire, which all reviewers are required to complete and submit.
The American Heart Association makes every effort to avoid any actual or potential conflicts of interest that may arise as a result of an outside relationship or a personal, professional, or business interest of a member of the writing panel.
Specifically, all members of the writing group are required to complete and submit a Disclosure Questionnaire showing all such relationships that might be perceived as real or potential conflicts of interest.
To purchase additional reprints, call — or e-mail kelle. Genetic basis for congenital heart disease: revisited: a scientific statement from the American Heart Association.
DOI: The expert peer review of AHA-commissioned documents eg, scientific statements, clinical practice guidelines, systematic reviews is conducted by the AHA Office of Science Operations.
Author manuscript; available in PMC Nov Lacro , MD, Amy L. Priest , MD, William T. Author information Copyright and License information Disclaimer.
Copyright notice. The publisher's final edited version of this article is available at Circulation. This article has been corrected.
See Circulation. See other articles in PMC that cite the published article. Abstract This review provides an updated summary of the state of our knowledge of the genetic contributions to the pathogenesis of congenital heart disease.
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He has appeared in more than 60 films since From Wikipedia, the free encyclopedia. Polish actor. This biography of a living person needs additional citations for verification.
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There is an increased risk of many aneuploidies with increasing maternal age. Increasingly, aneuploidies are detected prenatally with noninvasive prenatal diagnostic screening, and in this section, aneuploidies commonly associated with congenital HD such as Down syndrome and Turner syndrome are presented.
Information on other aneuploidies is present in the Appendix. Less common aneuploidies such as trisomy 8 and 9 survive to term only when they are mosaic.
Fetal echocardiograms allow for early and accurate diagnosis of the cardiac anatomy when aneuploidies are detected. Down syndrome is the most common aneuploidy and is usually caused by trisomy It is also the most common chromosome abnormality associated with congenital HD.
Individuals with Down syndrome often experience a gradual decline in cognition and have an increased risk of Alzheimer disease.
Health supervision guidelines are available and treatment is based on specific clinical manifestations. Among those patients undergoing staged single-ventricle palliation, individuals with Down syndrome had higher in-hospital mortality rates.
The risk of having a child with Down syndrome increases with advanced maternal age. Most individuals with Down syndrome have trisomy 21, but rarely, Down syndrome results from a translocation of chromosome 21 with another chromosome commonly 21, 14, or 13 or mosaicism in a subset of cells.
However, in general for individuals with mosaicism, the lower the level of mosaicism for trisomy 21, the less severe the cognitive deficits are.
Turner syndrome is another common chromosomal condition, caused by loss of part or all of an X chromosome in females. The most common features of Turner syndrome include short stature, early loss of ovarian function manifesting as delayed puberty and delayed menarche and in adult women, anovulation and infertility , lymphedema, webbed neck, low posterior hairline, cubitus valgus, congenital HD, skeletal anomalies, renal anomalies, and developmental delays, nonverbal learning disabilities, and behavioral problems in some girls.
Treatment with growth hormone is often beneficial, ideally beginning in early childhood, and can increase final adult height by 8 to 10 cm.
Estrogen replacement therapy is usually started at the time of normal puberty, around 12 years of age, to initiate normal timing of breast development and to help prevent osteoporosis.
Estrogen and progesterone are given to support menstruation. Cardiac structural anomalies usually involve the left side of the heart and most commonly include BAV and coarctation of the aorta and less commonly partial anomalous pulmonary venous return and hypoplastic left heart syndrome HLHS.
All patients with Turner syndrome should have a baseline echocardiogram and cardiac evaluation and follow-up as necessary based on the baseline evaluation.
BAV, coarctation of the aorta, and systemic hypertension are associated with aortic dilatation and dissection.
The exact genetic abnormality found on karyotype analysis varies and can include classic 45,X but also individuals who are mosaic 45,X with another cell line, including 46,XX, 47,XXX, or 46,XY, as well as individuals with structural abnormalities of the X chromosome, including deletions and translocations of the X chromosome.
Array CGH is useful to define precisely the extent of the deletions or translocation. For mosaic individuals, the phenotype is generally less severe as the percentage of 45,X cells decreases.
It is important to determine whether there are any cells with a Y chromosome using an SRY polymerase chain reaction test, because this can be associated with gonadal dysgenesis that might require surgical removal of gonadal tissue to prevent the increased risk of cancer.
CNVs range widely in size from single genes to large segmental deletions or duplications of millions of base pairs. In general, deletions are more deleterious than duplications because of the sensitivity in gene dosage for many genes that do not tolerate haploinsufficiency.
CNVs that encompass multiple genes can have a wide range of phenotypic effects because of the additive impact of individual genes on individual phenotypes or the pleiotropic effects of single genes on multiple phenotypes.
Identification of the relevant gene for congenital HD within a CNV interval requires mapping of multiple patients with overlapping CNVs to identify a critical interval and ultimately a single gene within the critical interval that is associated consistently with congenital HD.
Additional supportive evidence for the congenital HD gene is provided by examples of patients with point mutations within that single gene within the critical region who have congenital HD.
At least part of the explanation for the worse outcome could be an association with extracardiac manifestations that impact medical care.
In one series of 58 patients with congenital HD and other dysmorphic features or other anomalies, Many new CNVs associated with congenital HD have been identified over the past 10 years and now have been observed in sufficient numbers of patients to define the clinical features associated with them.
There are several common principles that apply across the CNVs. Each of the CNVs includes contiguous gene deletions or duplications, and generally deletions are associated with greater severity of neurocognitive phenotype.
Because each of the CNVs includes multiple genes, it is not always clear whether the overall phenotype is caused by the effects of multiple genes on multiple aspects of the phenotype or whether certain single genes within the interval have pleiotropic effects on multiple aspects of the phenotype.
It is usually unclear what the other determinants of congenital HD are, but it is likely that they are interacting with genetic factors either on the opposite allele or genetic variants in cis on the same chromosome or in trans on other chromosomes, as well as nongenetic factors.
Most CNVs are associated with effects on behavior and cognition, and many are associated with growth effects that are independent of the congenital HD and are important to appreciate when assessing clinical outcomes.
In this section, several CNVs are highlighted. The Appendix provides information on other less frequent CNVs. The 22q Frequent clinical features include dysmorphic facies, congenital HD especially conotruncal malformations and aortic arch anomalies , palatal malformations, learning difficulties, and immunodeficiency.
Facial features are characteristic but can be relatively subtle, especially in infants. Facial dysmorphisms include myopathic facies, tubular nose with bulbous nasal tip, hypoplastic alae nasi, and low-set or dysplastic ears.
Additional findings include hypocalcemia, significant feeding and swallowing problems including regurgitation through the nose , constipation, renal anomalies, hearing loss, laryngotracheoesophageal anomalies, growth hormone deficiency, autoimmune disorders, seizures, central nervous system anomalies, skeletal abnormalities, ophthalmologic abnormalities, enamel hypoplasia, and malignancies rare.
Behavioral and learning disabilities become more evident in school-aged children, whereas psychiatric disorders often become manifest in adolescence and adulthood Table 2.
Delays in emergence of language, intellectual disability, and learning differences nonverbal learning disability with verbal IQ significantly greater than the performance IQ are common.
Attention deficit disorder, anxiety, perseveration, and difficulty with social interactions are also common. The estimated prevalence of the 22q The majority of 22q It is important to identify the cardiac patient with a 22q For example, there is a higher operative mortality in some patients with 22q Affected individuals should receive leukocyte-depleted and cytomegalovirus-negative blood products to prevent serious graft-versus-host disease or overwhelming infection.
Given the frequency of 22q Clinical assessment for syndromic features alone might not consistently identify the infant carrying a 22q11 deletion, because facial features can evolve with time.
Therefore, routine screening of individuals with selected types of congenital HD using CMA is warranted either prenatally or postnatally.
The estimated 22q Among those with tetralogy of Fallot, the strongest association with 22q Aortic root dilation has been described with 22q Deletion of several genes within this region contributes to the cardiac and noncardiac features.
The size of the deletion can be precisely determined by CMA. Smaller or larger deletions can contribute to atypical clinical phenotypes.
Mutations outside the interval or on the nondeleted 22q An example of this is Bernard-Soulier syndrome, an autosomal recessive trait, which includes giant platelets, thrombocytopenia, and a prolonged bleeding time.
Several cases of Bernard-Soulier syndrome have been reported in which a 22q Although rare, the occurrence of these 2 conditions together can potentially place the 22q Duplication of the same 22q Generally, the duplication is associated with milder and more variable manifestations than the deletion.
The duplication can be either de novo or inherited from a phenotypically normal parent. Many of the reported series likely suffer from ascertainment bias compared with phenotypes in unselected population-based cohorts.
A small number of individuals have distal deletions of 1. Patients with the distal deletion share some overlapping neurobehavioral features, including speech delay and learning disabilities, with proximal 22q A recent study compared rare CNVs outside the common 22q Although there was no significant difference in the overall burden of rare CNVs, an overabundance of CNVs affecting cardiac-related genes was detected in 22q Williams-Beuren syndrome or Williams syndrome WS is a contiguous gene deletion syndrome caused by deletion at 7q Feeding difficulties during infancy often lead to poor weight gain.
Adults have short stature less than third percentile and tend to be overweight or obese and to have complications of systemic hypertension, diabetes mellitus, and diverticulosis.
Frequent cardiovascular anomalies include supravalvular aortic stenosis SVAS , often in combination with supravalvular pulmonary artery stenosis and branch pulmonary artery stenosis.
The SVAS can progress during childhood and is the most common abnormality requiring surgical intervention. In contrast, the branch pulmonary artery stenosis often regresses with time.
Any artery can be narrowed, including the ascending aorta, aortic arch, and descending thoracic and abdominal aorta, as well as central and peripheral arteries including the coronary arteries, carotid and cerebral arteries, mesenteric arteries, renal arteries, and pulmonary arteries.
Affected arteries typically have thickened walls and narrowed lumens. There is an increased risk of anesthesia-related complications and sudden cardiac death.
Risk factors include myocardial ischemia attributable to coronary stenosis or severe biventricular outflow tract obstruction, but the causative mechanisms have not been fully delineated.
As with other contiguous gene deletion syndromes, WS has a broad range of phenotypic variability. Although there is wide phenotypic variability even among individuals with the typical deletion, smaller or larger deletions might contribute to atypical clinical phenotypes.
Given the clinical variability of WS and the fact that the physical and developmental signs can be relatively subtle during infancy, it is not unusual for the diagnosis to be confirmed only after identification of a characteristic cardiovascular defect such as SVAS.
The severity of SVAS and other vascular defects tends to be greater in males, and infants and children with more severe vascular involvement tend to be diagnosed with WS at younger ages than those with trivial or no cardiovascular involvement.
Because SVAS is very common in WS and uncommon in the general population, it is appropriate to consider testing all patients with SVAS at the time of diagnosis of the cardiovascular defect.
Furthermore, if peripheral pulmonary artery stenosis persists beyond infancy, it is also appropriate to consider testing for WS.
Similarly, if any of the defects associated with the elastin arteriopathy, including coronary artery ostial stenosis, renal artery stenosis, and middle aortic syndrome abdominal coarctation , are diagnosed at any age, testing for WS should be considered.
Of note, CNVs in the 7q Early diagnosis of WS is important to optimize management of other potential medical problems Table 4.
Hypercalcemia occurs most commonly in the first year of life, whereas hypercalciuria can persist and occur at any age.
Hypercalcemia can lead to nephrocalcinosis and renal failure. Obesity, abnormal oral glucose tolerance tests, and diabetes mellitus are common, especially in adults.
Intellectual disability is common and usually mild, but with a specific cognitive profile with strengths in verbal short-term memory and language and extreme weakness in visuospatial constructive cognition.
Attention deficit disorder and anxiety are common. JS is a clinically recognizable contiguous gene deletion syndrome involving deletions from subband 11q23 to the telomere, ranging in size from 7 to 16 Mb.
Clinical manifestations include dysmorphic features, growth retardation sometimes associated with IGF-1 insulin-like growth factor 1 deficiency, cognitive and behavioral dysfunction, congenital HD, thrombocytopenia and platelet dysfunction Paris-Trousseau syndrome , recurrent infections, immune deficiency, and ophthalmologic, gastrointestinal, and genitourinary problems.
A prospective study of patients with the 11q terminal deletion disorder, diagnosed by karyotype rather than CMA, provided detailed delineation of the clinical manifestations, as well as a comprehensive set of recommendations for the clinical management of patients with this disorder.
More than half of affected individuals have congenital HD, most of whom require surgical intervention. About one-third of patients with heart defects have a membranous VSD, and another third have left ventricular outflow tract defects with various degrees of hypoplasia or obstruction of the mitral valve, left ventricle, aortic valve, or aorta.
The prevalence of JS is estimated to be 1 in to 1 in live births. Through a combination of human genetic techniques and using genetically engineered animal models, ETS1 has been identified as the causal gene for congenital HD in JS.
Most recently, a patient with a complex congenital HD including mitral atresia and hypoplastic left ventricle was found to carry a de novo frameshift mutation in ETS1 , likely a loss-of-function mutation, providing further confirmation that loss of ETS1 is the cause of congenital HD in JS.
There is no correlation between the size of the deletion and whether or not there is congenital HD or what the specific congenital HD is.
Nearly all patients with JS have Paris-Trousseau syndrome, characterized by thrombocytopenia and platelet dysfunction, and heterozygous loss of the FLI1 gene has been identified as the cause.
Platelet dysfunction persists in older individuals, despite normal platelet counts. Risk for bleeding is one of the most common causes of mortality in JS and likely places these patients at increased risk for the development of brain hemorrhages.
Cognitive function ranges from normal intelligence to moderate cognitive disability. Nearly half of the patients have mild cognitive disability, with a characteristic neuropsychiatric profile demonstrating near-normal receptive language ability but mild to moderate impairment in expressive language, with full-scale IQs typically in the 60s to 70s.
Individuals with suspected or confirmed JS should have a thorough genetics evaluation. The extent of the deletion can be precisely delineated by CMA in the proband.
Patients with JS require coordinated multisystem care. A cardiac evaluation including an echocardiogram is recommended at baseline and as needed.
Careful monitoring of the platelet count is necessary in infancy and early childhood, and once the platelet count normalizes, platelet function studies should be evaluated periodically.
Neurocognitive and behavioral difficulties are common. Baseline and ongoing evaluations by a neuropsychologist and behavioral specialist are recommended, as well as brain imaging at baseline and as needed.
Patients should be screened for ophthalmologic issues including exotropia, amblyopia, refractive errors, ptosis, and retinal artery tortuosity.
Common gastrointestinal issues include failure to thrive, constipation, and pyloric stenosis.
Genitourinary anomalies include cryptorchidism and renal anomalies. A baseline renal ultrasound is recommended. The 1p36 deletion syndrome is the second most common deletion syndrome.
Clinical features include dysmorphic facies, intellectual disability ranging from mild to severe, hypotonia, seizures, structural brain abnormalities, congenital heart defects, ophthalmologic and vision issues, hearing loss, skeletal abnormalities, and genitourinary anomalies.
Behavioral disorders include autism, tantrums, self-mutilation, stereotypies, and hyperphagia. Structural brain abnormalities include dilation of the lateral ventricles, cortical atrophy, and hypoplasia or agenesis of the corpus callosum.
Seizures are present in approximately half of the individuals with the 1p36 deletion. The prevalence of 1q36 deletion is 1 in to births, with a female-to-male ratio.
This condition is identified by CMA testing. Recurrent 1. The associated psychiatric and behavioral anomalies include autistic spectrum disorder, attention deficit hyperactivity disorder, mood disorder, and sleep disturbances.
The prevalence of the 1q The condition is identified by CMA. The gene responsible for congenital HD within the interval is possibly GJA5, which encodes for a cardiac gap junction protein connexin The reciprocal duplication of 1q There is a tendency toward larger head size.
Some individuals have neurobehavioral manifestations, including intellectual disabilities, developmental delay, expressive language delay, learning disabilities, features of autism, or attention deficit hyperactivity disorder, but others have no neurobehavioral problems.
Deletions of 8p There are also several reported cases of more complex cardiac anatomy including hypoplastic right ventricle, double-outlet right ventricle, and double-inlet left ventricle.
Table 5 can be consulted for details of multiple other genetic syndromes. Alagille syndrome ALGS is an autosomal dominant syndromic disorder characterized by cardiovascular, hepatic, orthopedic, and ophthalmologic complications.
Children with ALGS have a prominent forehead, deeply set eyes, hypertelorism, straight nose with a bulbous tip, and pointed chin.
There is considerable intrafamilial and interfamilial variability in the hepatic complications of ALGS, and some individuals have no detectable liver disease.
The most common complications are chronic cholestasis, elevated liver enzymes, hypercholesterolemia, or liver failure.
The typical pathological finding is paucity of the bile ducts on liver biopsy. Additional complications include Axenfeld anomaly, Rieger anomaly, optic disk drusen, and retinal pigmentary changes.
Less commonly reported skeletal features include hemivertebrae, spina bifida occulta, and rib anomalies. Two-thirds of those with ALGS have peripheral or branch pulmonary stenosis or other arterial narrowing aortic coarctation, renal artery, middle aortic syndrome, Moya-moya, basilar, and middle cerebral arteries.
There is no known racial or ethnic predilection for ALGS. There is an estimated incidence of to live births.
Overall, there are no differences in the cardiovascular phenotype based on causative gene or mutation type sequence variant versus deletion.
However, there have been 2 variants reported for which affected individuals had cardiac but not liver disease, and further analysis demonstrated that the amount of JAG1 protein produced was more than in other ALGS variants but less than in wild type.
Holt-Oram syndrome HOS is an autosomal dominant disorder often referred to as heart-hand syndrome because of the 2 most common features: congenital HD and radial ray defects.
Radial ray abnormalities can be unilateral or bilateral and, when bilateral, can be symmetrical or asymmetrical.
The penetrance of upper limb anomalies in HOS is complete but ranges from subtle carpal abnormalities without functional consequence only seen by radiogram to complete phocomelia the hand attached close to the trunk.
Other reported abnormalities include triphalangeal thumb, absent thumb, radius hypoplasia or aplasia, and radioulnar synostosis.
Because there is considerable intrafamilial phenotypic variability, a family history of a first-degree relative with a septal defect, cardiac conduction disease, or radial ray abnormality can provide a clue to the diagnosis.
Three quarters of those with HOS have congenital HD, most commonly involving the atrial or ventricular septum.
ASDs can present as common atrium, often with atrial isomerism. Sinus bradycardia, first-degree atrioventricular heart block, and complete heart block with or without atrial fibrillation are all reported coincident with or subsequent to the time of congenital HD diagnosis if present.
HOS has an estimated prevalence of between 0. TBX5 is a transcription factor and is an essential regulator of limb and cardiac development, particularly the cardiac septum and conduction system.
Flat midface, flat nasal bridge, broad nasal tip, hypertelorism, down-slanting palpebral fissures, mild ptosis, short philtrum, and everted lips are among the recognizable facial features.
Aplasia or hypoplasia of the middle phalanges of the fifth fingers is part of the diagnostic triad along with typical facial features and PDA of Char syndrome.
Case reports indicate a number of additional features can be seen in Char syndrome, including hypodontia, foot anomalies joint fusion, clinodactyly, polydactyly, syndactyly , strabismus, and other hand anomalies interstitial polydactyly, distal symphalangism of the fifth fingers, and third finger hypoplasia.
The primary cardiac finding is PDA. The prevalence has not been determined, but it is thought to be quite rare.
Approximately half of families who have the diagnostic triad of Char syndrome recognizable facial features, aplasia or hypoplasia of the middle phalanges of the fifth fingers, and PDA will have a heterozygous pathogenic variant in TFAP2B.
There are no known genotype-phenotype correlations with regard to cardiovascular complications. Ellis-van Creveld syndrome EVC is an autosomal recessive skeletal dysplasia associated with a characteristic cardiac finding of a primary atrial septation defect resulting in a common atrium.
Individuals with EVC can have a characteristic appearance of the mouth, with a short upper lip bound by frenula to the alveolar ridge.
A variety of dental abnormalities are reported, including natal teeth, partial adontia, small teeth, delayed tooth eruption, conical teeth, and enamel hypoplasia.
The nails are often hypoplastic, and hair can be scant or fine. There is prenatal-onset short stature; adult stature is in the range of 43 to 60 inches.
The characteristic skeletal findings include postaxial polydactyly, usually of the hands, short limbs with increasing severity from the proximal to distal portions of the limbs , and short ribs.
Hand radiographs often show short, broad middle phalanges and hypoplastic distal phalanges, and sometimes carpal bone abnormalities.
The worldwide prevalence is not known. There is a founder mutation among the Amish, and large kindreds from Mexico, Ecuador, and Brazil that have also been reported.
No cardiovascular genotype-phenotype correlations have been reported. Adams-Oliver syndrome AOS is an inherited malformation syndrome in which cardiac, scalp, and limb defects are present.
There is genetic heterogeneity, with both autosomal dominant and autosomal recessive forms. There is considerable variability in the extent of aplasia cutis congenita in affected individuals, ranging from total absence of an area of scalp skin and skull to vertex hairless patches.
Limb defects can include terminal transverse reduction defects of hands or feet, short distal phalanges, syndactyly, ectrodactyly, and polydactyly.
There is an estimated incidence of 0. Six genes are currently involved in the pathogenesis of AOS. Kabuki syndrome KS has both X-linked and autosomal dominant pathogeneses.
The syndrome is characterized by specific facial features, skeletal anomalies, congenital HD, renal anomalies, intellectual disability, and growth deficiency.
Children with KS have long palpebral fissures, eversion of lateral one-third of the lower eyelid, arched eyebrows with sparse lateral third, large dysplastic ears, cleft palate, and depressed nasal tip.
There can be associated autism spectrum disorder, communication difficulties, and repetitive behavior. Cryptorchidism, duplicated collecting system, single fused kidney, and hypospadias have been reported.
The prevalence in Japan was estimated at , as the initial patients described were Japanese. A minimum birth incidence of in Australia and New Zealand has been calculated.
A preponderance of males compared with females with left-sided obstructive lesions has been described among KMT2D patients.
The acronymic name of this condition includes C for coloboma, H for heart defects, A for choanal atresia, R for retarded growth and development, G for genital anomalies, and E for ear anomalies.
Diagnostic criteria are helpful in determining a clinical diagnosis for individuals suspected of having CHARGE syndrome. Characteristic facial features can include orofacial clefts, unilateral or bilateral facial palsy, and malformed protruding ear pinnae.
Marked developmental delay is usual. Motor skills are delayed with hypotonia. Delayed language development can result from hearing loss and reduced vision.
Vision is variably affected by the colobomas. Hearing loss is extremely common and varies from mild to profound. Individuals can have severe swallowing difficulties, aspiration problems, gastroesophageal reflux, and tracheoesophageal fistula.
Feeding problems are very common, and gastrostomy feeding measures are often required. Males can have cryptorchidism and micropenis, and both males and females can have hypogonadotropic hypogonadism.
Hand anomalies including polydactyly and occasional scoliosis are possible. Some families in which there are affected siblings and unaffected parents are likely examples of gonadal mosaicism.
The RASopathies are a group of autosomal dominant disorders with overlapping cardiac, growth, facial, and neurodevelopmental features.
Somatic mutations in genes in the pathway have long been known to cause hematologic cancers and solid tumors.
More recently, germline sequence variants have been found to cause Noonan syndrome NS and other uncommon phenotypically related disorders, including cardiofaciocutaneous syndrome CFC , Costello syndrome CS , and Noonan syndrome with multiple lentigines NSML.
Collectively, these disorders are termed the RASopathies. Individuals with NS have characteristic facial features and structural and functional abnormalities involving multiple organ syndromes and a high incidence of cardiac abnormalities.
The facial features of NS change with age. In adulthood, the features are most often mild, although some adults retain significant, readily recognizable dysmorphisms.
Early feeding problems related to hypotonia and delayed gastrointestinal motor development, gastroesophageal reflux, chronic constipation, and intestinal malrotation respond well to medical management and feeding therapy.
The most common endocrine complications include hypothyroidism, pubertal delay, and short stature. The pathogenesis for the short stature can be nutritional, attributable to growth hormone deficiency, or attributable to growth hormone insensitivity.
Looking across studies, there is a mean gain in height of 9. Coagulation factor deficiencies, thrombocytopenia, and platelet aggregation abnormalities have all been reported ; however, only a small proportion of those with abnormalities on coagulation testing have functional bleeding problems.