Human Genetics of Atrioventricular Septal Defect.

Atrioventricular septal defects (AVSD), also known as a common atrioventricular canal (CAVC), are clinically severe heart malformations that affect about 1 out of every 2100 live births. AVSD makes up about 5% of all congenital heart defects. AVSD is associated with cytogenetic disorders such as Down syndrome and numerous other rare genetic syndromes, but also occurs as a simplex trait. Studies in mouse models have identified over 100 genetic mutations that have the potential to cause an AVSD. However, studies in humans indicate that AVSD is genetically heterogeneous, and that the cause in humans is very rarely a single-gene defect. Familial cases do occur albeit rarely, usually with autosomal dominant inheritance and variable expression. In addition, the frequent occurrence of AVSD in some syndromes with known genetic causes such as heterotaxy syndrome points to additional genes/pathways that increase AVSD risk. Accordingly, while the genetic underpinnings for most AVSD remain unknown, there have been advances in identifying genetic risk factors for AVSD in both syndromic and nonsyndromic cases. This chapter summarizes the current knowledge of the genetic basis for AVSD.

Identification of novel rare copy number variants associated with sporadic tetralogy of Fallot and clinical implications.

Tetralogy of Fallot (TOF) is the most common cyanotic congenital heart disease. Highly penetrant copy number variants (CNVs) and genes related to the etiology of TOF likely exist with differences among populations. We aimed to identify CNV contributions to sporadic TOF cases in Han Chinese. Genomic DNA was extracted from peripheral blood in 605 subjects (303 sporadic TOF and 302 unaffected Han Chinese [Control] from cardiac centers in China) and analyzed by genome-wide association study (GWAS). The GWAS results were compared with existing Database of Genetic Variants. These CNVs were further validated by qPCR. Bioinformatics analyses were performed with protein-protein interaction (PPI) network and KEGG pathway enrichment. Across all chromosomes 119 novel "TOF-specific CNVs" were identified with prevalence of CNVs of 21.5% in chromosomes 1-20 and 37.0% including Chr21/22. In chromosomes 1-20, CNVs on 11q25 (encompasses genes ACAD8, B3GAT1, GLB1L2, GLB1L3, IGSF9B, JAM3, LOC100128239, LOC283177, MIR4697, MIR4697HG, NCAPD3, OPCML, SPATA19, THYN1, and VPS26B) and 14q32.33 (encompasses genes THYN1, OPCML, and NCAPD3) encompass genes most likely to be associated with TOF. Specific CNVs found on the chromosome 21 (6.3%) and 22(11.9%) were also identified in details. PPI network analysis identified the genes covering the specific CNVs related to TOF and the signaling pathways. This study for first time identified novel TOF-specific CNVs in the Han Chinese with higher frequency than in Caucasians and with 11q25 and 14q32.33 not reported in TOF of Caucasians. These novel CNVs identify new candidate genes for TOF and provide new insights into genetic basis of TOF.

DNA Methylation Analysis of Turner Syndrome BAV.

Turner Syndrome (TS) is a rare cytogenetic disorder caused by the complete loss or structural variation of the second sex chromosome. The most common cause of early mortality in TS results from a high incidence of left-sided congenital heart defects, including bicuspid aortic valve (BAV), which occurs in about 30% of individuals with TS. BAV is also the most common congenital heart defect in the general population with a prevalence of 0.5-2%, with males being three-times more likely to have a BAV than females. TS is associated with genome-wide hypomethylation when compared to karyotypically normal males and females. Alterations in DNA methylation in primary aortic tissue are associated with BAV in euploid individuals. Here we show significant differences in DNA methylation patterns associated with BAV in TS found in peripheral blood by comparing TS BAV (n = 12), TS TAV (n = 13), and non-syndromic BAV (n = 6). When comparing TS with BAV to TS with no heart defects we identified a differentially methylated region encompassing the BAV-associated gene MYRF, and enrichment for binding sites of two known transcription factor contributors to BAV. When comparing TS with BAV to euploid women with BAV, we found significant overlapping enrichment for ChIP-seq transcription factor targets including genes in the NOTCH1 pathway, known for involvement in the etiology of non-syndromic BAV, and other genes that are essential regulators of heart valve development. Overall, these findings suggest that altered DNA methylation affecting key aortic valve development genes contributes to the greatly increased risk for BAV in TS.

Cardiovascular Outcomes in Aortopathy: GenTAC Registry of Genetically Triggered Aortic Aneurysms and Related Conditions.

BACKGROUND: The GenTAC (Genetically Triggered Thoracic Aortic Aneurysm and Cardiovascular Conditions) Registry enrolled patients with genetic aortopathies between 2007 and 2016. OBJECTIVES: The purpose of this study was to compare age distribution and probability of elective surgery for proximal aortic aneurysm, any dissection surgery, and cardiovascular mortality among aortopathy etiologies. METHODS: The GenTAC study had a retrospective/prospective design. Participants with bicuspid aortic valve (BAV) with aneurysm (n = 879), Marfan syndrome (MFS) (n = 861), nonsyndromic heritable thoracic aortic disease (nsHTAD) (n = 378), Turner syndrome (TS) (n = 298), vascular Ehlers-Danlos syndrome (vEDS) (n = 149), and Loeys-Dietz syndrome (LDS) (n = 121) were analyzed. RESULTS: The 25% probability of elective proximal aortic aneurysm surgery was 30 years for LDS (95% CI: 18-37 years), followed by MFS (34 years; 95% CI: 32-36 years), nsHTAD (52 years; 95% CI: 48-56 years), and BAV (55 years; 95% CI: 53-58 years). Any dissection surgery 25% probability was highest in LDS (38 years; 95% CI: 33-53 years) followed by MFS (51 years; 95% CI: 46-57 years) and nsHTAD (54 years; 95% CI: 51-61 years). BAV experienced the largest relative frequency of elective surgery to any dissection surgery (254/33 = 7.7), compared with MFS (273/112 = 2.4), LDS (35/16 = 2.2), or nsHTAD (82/76 = 1.1). With MFS as the reference population, risk of any dissection surgery or cardiovascular mortality was lowest in BAV patients (HR: 0.13; 95% CI: 0.08-0.18; HR: 0.13; 95%: CI: 0.06-0.27, respectively). The greatest risk of mortality was seen in patients with vEDS. CONCLUSIONS: Marfan and LDS cohorts demonstrate age and event profiles congruent with the current understanding of syndromic aortopathies. BAV events weigh toward elective replacement with relatively few dissection surgeries. Nonsyndromic HTAD patients experience near equal probability of dissection vs prophylactic surgery, possibly because of failure of early diagnosis.

A Review of Recent Developments in Turner Syndrome Research.

Turner syndrome is a rare disorder resulting from complete or partial loss of the second sex chromosome. Common manifestations include delayed growth, premature ovarian failure, congenital heart defects, endocrine disorders, lymphedema, and webbed neck. People with Turner syndrome have significantly increased mortality risk primarily due to cardiovascular abnormalities. The mechanisms that lead to these defects are not completely understood and are obscured by the significant variability of both karyotype and phenotype without consistent correlation between the two. This paper presents a review of the recent literature surrounding the symptoms, mechanisms, diagnosis, and treatment of Turner syndrome with a focus on cardiovascular manifestations. With technological advancements in genetics, the molecular processes of Turner syndrome have begun to be dissected. Certain genes on the X chromosome that typically escape inactivation have been implicated in both specific manifestations and broader risk categories. Recently identified genome-wide epigenetic changes may help explain the variability in presentation. It remains unclear as to how the combination of these factors results in the overall clinical picture, but advances in genomic, genetic, epigenetic, and -omics technology hold promise for providing insights that will improve the medical management of individuals with Turner syndrome.

Identifying genetic factors that contribute to the increased risk of congenital heart defects in infants with Down syndrome.

Atrioventricular septal defects (AVSD) are a severe congenital heart defect present in individuals with Down syndrome (DS) at a > 2000-fold increased prevalence compared to the general population. This study aimed to identify risk-associated genes and pathways and to examine a potential polygenic contribution to AVSD in DS. We analyzed a total cohort of 702 individuals with DS with or without AVSD, with genomic data from whole exome sequencing, whole genome sequencing, and/or array-based imputation. We utilized sequence kernel association testing and polygenic risk score (PRS) methods to examine rare and common variants. Our findings suggest that the Notch pathway, particularly NOTCH4, as well as genes involved in the ciliome including CEP290 may play a role in AVSD in DS. These pathways have also been implicated in DS-associated AVSD in prior studies. A polygenic component for AVSD in DS has not been examined previously. Using weights based on the largest genome-wide association study of congenital heart defects available (2594 cases and 5159 controls; all general population samples), we found PRS to be associated with AVSD with odds ratios ranging from 1.2 to 1.3 per standard deviation increase in PRS and corresponding liability r2 values of approximately 1%, suggesting at least a small polygenic contribution to DS-associated AVSD. Future studies with larger sample sizes will improve identification and quantification of genetic contributions to AVSD in DS.

Open Thoracoabdominal Aortic Repair in Patients With Heritable Aortic Disease in the GenTAC Registry.

BACKGROUND: Although patients with various types of heritable aortopathy often require distal aortic repair, data are limited regarding the most extensive operations-open thoracoabdominal aortic aneurysm (TAAA) repairs. The objective of this multicenter registry study was to characterize TAAA repairs in a large cohort of patients with different heritable aortic diseases. METHODS: From the 3699 patients enrolled at 8 participating centers in the Genetically Triggered Thoracic Aortic Aneurysms and Cardiovascular Conditions (GenTAC) Registry, we identified 155 open TAAA repairs in 142 unique patients. We examined data related to clinical characteristics, surgical techniques, and outcomes. RESULTS: The primary diagnoses included Marfan syndrome (n = 76; 54%), familial thoracic aortic aneurysm and dissections (n = 31; 22%), and Loeys-Dietz syndrome (n = 10; 7%). Most repairs were performed for aneurysms associated with aortic dissection (n = 110; 71%). The most common repairs involved the entire descending thoracic aorta with distal extension (21% Crawford extent I and 36% extent II). Adjuncts used during repair varied substantially. The operative mortality rate was 1.3%. Other complications included paraplegia (4%), acute renal failure (5%), and vocal cord paralysis (21%). Reoperation after TAAA repair was required in a subset of cases for early bleeding (n = 15; 10%) and late repair failure (n = 7; 5%). CONCLUSIONS: Open TAAA repairs are necessary in a variety of heritable aortic diseases. These patients often require extensive surgical repair, and a variety of adjunctive techniques are utilized. The risk of repair failure and the need for reoperation in a subset of patients support the need for vigilant long-term surveillance after repair.

The genetic basis of Turner syndrome aortopathy.

Our goal is to identify the genetic underpinnings of bicuspid aortic valve and aortopathy in Turner syndrome. We performed whole exome sequencing on 188 Turner syndrome study subjects from the GenTAC registry. A gene-based burden test, SKAT-O, was used to evaluate the data using bicuspid aortic valve (BAV) and aortic dimension z-scores as covariates. This revealed that TIMP3 was associated with BAV and increased aortic dimensions at exome-wide significance. It had been previously shown that genes on chromosome Xp contribute to aortopathy when hemizygous. Our analysis of Xp genes revealed that hemizygosity for TIMP1, a functionally redundant paralogue of TIMP3, increased the odds of having BAV aortopathy compared to individuals with more than one TIMP1 copy. The combinatorial effect of a single copy of TIMP1 and TIMP3 risk alleles synergistically increased the risk for BAV aortopathy to nearly 13-fold. TIMP1 and TIMP3 are tissue inhibitors of matrix metalloproteinases (TIMPs) which are involved in development of the aortic valve and protection from thoracic aneurysms. We propose that the combination of TIMP1 haploinsufficiency and deleterious variants in TIMP3 significantly increases the risk of BAV aortopathy in Turner syndrome, and suggest that TIMP1 hemizygosity may play a role in euploid male aortic disease.

Conference summary: What we have learned and where we are headed.

This overview highlights the actionable near-term objectives for the TRN drawn from discussions in the breakout sessions. A major purpose of the symposium was to focus attention on establishing priorities, setting goals, and identifying the steps toward accomplishing those goals. Two major objectives were identified. One is to establish Turner syndrome as a priority area of research for the National Institutes of Health. Turner syndrome should not only be viewed as a rare disorder, but also as a model for common diseases that have a male sex bias in the general population attributable to the lack of a second X chromosome. Barriers to recognition of Turner syndrome as an important area of research were identified, and new approaches to enhancing visibility are discussed. The second major objective is to further development of the Turner Syndrome Research Registry (TSRR). This patient-powered research registry is a paradigm-shifting model for how human-based research can be improved through equal partnerships between researchers and study subjects. The TSRR is founded on an agreement that study participants are the ultimate owners of their personal data. The major challenges to establishing a maximally functional registry of this design were discussed, and a clear path forward was established.

Associations Between Medical History, Cognition, and Behavior in Youth With Down Syndrome: A Report From the Down Syndrome Cognition Project.

The cause of the high degree of variability in cognition and behavior among individuals with Down syndrome (DS) is unknown. We hypothesized that birth defects requiring surgery in the first years of life (congenital heart defects and gastrointestinal defects) might affect an individual's level of function. We used data from the first 234 individuals, age 6-25 years, enrolled in the Down Syndrome Cognition Project (DSCP) to test this hypothesis. Data were drawn from medical records, parent interviews, and a cognitive and behavior assessment battery. Results did not support our hypothesis. That is, we found no evidence that either birth defect was associated with poorer outcomes, adjusting for gender, race/ethnicity, and socioeconomic status. Implications for study design and measurement are discussed.

TIMP3 and TIMP1 are risk genes for bicuspid aortic valve and aortopathy in Turner syndrome.

Turner syndrome is caused by complete or partial loss of the second sex chromosome, occurring in ~1 in 2,000 female births. There is a greatly increased incidence of aortopathy of unknown etiology, including bicuspid aortic valve (BAV), thoracic aortic aneurysms, aortic dissection and rupture. We performed whole exome sequencing on 188 Turner syndrome participants from the National Registry of Genetically Triggered Thoracic Aortic Aneurysms and Cardiovascular Related Conditions (GenTAC). A gene-based burden test, the optimal sequence kernel association test (SKAT-O), was used to evaluate the data with BAV and aortic dimension z-scores as covariates. Genes on chromosome Xp were analyzed for the potential to contribute to aortopathy when hemizygous. Exome analysis revealed that TIMP3 was associated with indices of aortopathy at exome-wide significance (p = 2.27 x 10(-7)), which was replicated in a separate cohort. The analysis of Xp genes revealed that TIMP1, which is a functionally redundant paralogue of TIMP3, was hemizygous in >50% of our discovery cohort and that having only one copy of TIMP1 increased the odds of having aortopathy (OR = 9.76, 95% CI = 1.91-178.80, p = 0.029). The combinatorial effect of a single copy of TIMP1 and TIMP3 risk alleles further increased the risk for aortopathy (OR = 12.86, 95% CI = 2.57-99.39, p = 0.004). The products of genes encoding tissue inhibitors of matrix metalloproteinases (TIMPs) are involved in development of the aortic valve and protect tissue integrity of the aorta. We propose that the combination of X chromosome TIMP1 hemizygosity and variants of its autosomal paralogue TIMP3, significantly increases the risk of aortopathy in Turner syndrome.

Recent Advances in Placenta-Heart Interactions.

Congenital heart defects (CHD) occur in ∼1 in every 100 live births. In addition, an estimated 10% of fetal loss is due to severe forms of CHD. This makes heart defects the most frequently occurring birth defect and single cause of in utero fatality in humans. There is considerable evidence that CHD is heritable, indicating a strong contribution from genetic risk factors. There are also known external environmental exposures that are significantly associated with risk for CHD. Hence, the majority of CHD cases have long been considered to be multifactorial, or generally caused by the confluence of several risk factors potentially from genetic, epigenetic, and environmental sources. Consequently, a specific cause can be very difficult to ascertain, although patterns of associations are very important to prevention. While highly protective of the fetus, the in utero environment is not immune to insult. As the conduit between the mother and fetus, the placenta plays an essential role in maintaining fetal health. Since it is not a fully-formed organ at the onset of pregnancy, the development of the placenta must keep pace with the growth of the fetus in order to fulfill its critical role during pregnancy. In fact, the placenta and the fetal heart actually develop in parallel, a phenomenon known as the placenta-heart axis. This leaves the developing heart particularly vulnerable to early placental insufficiency. Both organs share several developmental pathways, so they also share a common vulnerability to genetic defects. In this article we explore the coordinated development of the placenta and fetal heart and the implications for placental involvement in the etiology and pathogenesis of CHD.

Analysis of Copy Number Variants on Chromosome 21 in Down Syndrome-Associated Congenital Heart Defects.

One in five people with Down syndrome (DS) are born with an atrioventricular septal defect (AVSD), an incidence 2000 times higher than in the euploid population. The genetic loci that contribute to this risk are poorly understood. In this study, we tested two hypotheses: (1) individuals with DS carrying chromosome 21 copy number variants (CNVs) that interrupt exons may be protected from AVSD, because these CNVs return AVSD susceptibility loci back to disomy, and (2) individuals with DS carrying chromosome 21 genes spanned by microduplications are at greater risk for AVSD because these microduplications boost the dosage of AVSD susceptibility loci beyond a tolerable threshold. We tested 198 case individuals with DS+AVSD, and 211 control individuals with DS and a normal heart, using a custom microarray with dense probes tiled on chromosome 21 for array CGH (aCGH). We found that neither an individual chromosome 21 CNV nor any individual gene intersected by a CNV was associated with AVSD in DS. Burden analyses revealed that African American controls had more bases covered by rare deletions than did African American cases. Inversely, we found that Caucasian cases had more genes intersected by rare duplications than did Caucasian controls. We also showed that previously DS+AVSD (DS and a complete AVSD)-associated common CNVs on chromosome 21 failed to replicate. This research adds to the swell of evidence indicating that DS-associated AVSD is similarly heterogeneous, as is AVSD in the euploid population.

Bicuspid and unicuspid aortic valves: Different phenotypes of the same disease? Insight from the GenTAC Registry.

BACKGROUND: Unicuspid aortic valve (UAV) is a rare disorder, often difficult to distinguish from bicuspid aortic valve (BAV). BAV and UAV share valve pathology such as the presence of a raphe, leaflet fusion, aortic stenosis, aortic regurgitation, and/or ascending aortic dilatation, but a comprehensive echocardiographic comparison of patients with UAV and BAV has not been previously performed. METHODS: We investigated UAV and BAV patients at an early stage of disease included in GenTAC, a national registry of genetically related aortic aneurysms and associated cardiac conditions. Clinical and echocardiographic data from the GenTAC Registry were compared between 17 patients with UAV and 17 matched-controls with BAV. RESULTS: Baseline characteristics including demographics, clinical findings including family history of BAV and aortic aneurysm/coarctation, and echocardiographic variables were similar between BAV and UAV patients; aortic stenosis was more common and more severe in patients with UAV. This was evidenced by higher mean and peak gradient, smaller aortic valve area, and more advanced valvular degeneration (all P < .05). There were no significant differences in aortic dimensions, with a similar pattern of enlargement of the ascending aorta. CONCLUSIONS: The similar baseline characteristics with more accelerated aortic valve degeneration and stenosis suggest that UAV represents an extreme in the spectrum of BAV syndromes. Therefore, it is reasonable to consider application of recommendations for the management of patients with BAV to those with the rarer UAV.

Associations of Age and Sex With Marfan Phenotype: The National Heart, Lung, and Blood Institute GenTAC (Genetically Triggered Thoracic Aortic Aneurysms and Cardiovascular Conditions) Registry.

BACKGROUND: The associations of age and sex with phenotypic features of Marfan syndrome have not been systematically examined in a large cohort of both children and adults. METHODS AND RESULTS: We evaluated 789 Marfan patients enrolled in the National Heart, Lung, and Blood Institute GenTAC (Genetically Triggered Thoracic Aortic Aneurysms and Cardiovascular Conditions) Registry (53% male; mean age 31 [range: 1-86 years]). Females aged ≥15 and males aged ≥16 years were considered adults based on average age of skeletal maturity. Adults (n=606) were more likely than children (n=183) likely to have spontaneous pneumothorax, scoliosis, and striae but were comparable in revised Ghent systemic score, ectopia lentis, and most phenotypic features, including prevalence of aortic root dilatation. Prophylactic aortic root replacement and mitral valve surgery were rare during childhood versus adulthood (2% versus 35% and 1% versus 9%, respectively, both P<0.0001). Adult males were more likely than females to have aortic root dilatation (92% versus 84%), aortic regurgitation (55% versus 36%), and to have undergone prophylactic aortic root replacement (47% versus 24%), all P<0.001. Prevalence of previous aortic dissection tended to be higher in males than females (25% versus 18%, P=0.06); 44% of dissections were type B. Type B dissection was strongly associated with previous prophylactic aortic root replacement. CONCLUSIONS: Pulmonary, skeletal, and aortic complications, but not other phenotypic features, are more prevalent in adults than children in Marfan syndrome. Aortic aneurysms and prophylactic aortic surgery are more common in men. Aortic dissection, commonly type B, occurs in an appreciable proportion of Marfan patients, especially in men and after previous prophylactic aortic root replacement.

Autosomal and X chromosome structural variants are associated with congenital heart defects in Turner syndrome: The NHLBI GenTAC registry.

Turner Syndrome (TS) is a developmental disorder caused by partial or complete loss of one sex chromosome. Bicuspid aortic valve and other left-sided congenital heart lesions (LSL), including thoracic aortic aneurysms and acute aortic dissections, are 30-50 times more frequent in TS than in the general population. In 454 TS subjects, we found that LSL are significantly associated with reduced dosage of Xp genes and increased dosage of Xq genes. We also showed that genome-wide copy number variation is increased in TS and identify a common copy number variant (CNV) in chromosome 12p13.31 that is associated with LSL with an odds ratio of 3.7. This CNV contains three protein-coding genes (SLC2A3, SLC2A14, and NANOGP1) and was previously implicated in congenital heart defects in the 22q11 deletion syndrome. In addition, we identified a subset of rare and recurrent CNVs that are also enriched in non-syndromic BAV cases. These observations support our hypothesis that X chromosome and autosomal variants affecting cardiac developmental genes may interact to cause the increased prevalence of LSL in TS. © 2016 Wiley Periodicals, Inc.

Cilia gene mutations cause atrioventricular septal defects by multiple mechanisms.

Atrioventricular septal defects (AVSDs) are a common severe form of congenital heart disease (CHD). In this study we identified deleterious non-synonymous mutations in two cilia genes, Dnah11 and Mks1, in independent N-ethyl-N-nitrosourea-induced mouse mutant lines with heritable recessive AVSDs by whole-exome sequencing. Cilia are required for left/right body axis determination and second heart field (SHF) Hedgehog (Hh) signaling, and we find that cilia mutations affect these requirements differentially. Dnah11avc4 did not disrupt SHF Hh signaling and caused AVSDs only concurrently with heterotaxy, a left/right axis abnormality. In contrast, Mks1avc6 disrupted SHF Hh signaling and caused AVSDs without heterotaxy. We performed unbiased whole-genome SHF transcriptional profiling and found that cilia motility genes were not expressed in the SHF whereas cilia structural and signaling genes were highly expressed. SHF cilia gene expression predicted the phenotypic concordance between AVSDs and heterotaxy in mice and humans with cilia gene mutations. A two-step model of cilia action accurately predicted the AVSD/heterotaxyu phenotypic expression pattern caused by cilia gene mutations. We speculate that cilia gene mutations contribute to both syndromic and non-syndromic AVSDs in humans and provide a model that predicts the phenotypic consequences of specific cilia gene mutations.

Penetrance of Congenital Heart Disease in a Mouse Model of Down Syndrome Depends on a Trisomic Potentiator of a Disomic Modifier.

Down syndrome (DS) is a significant risk factor for congenital heart disease (CHD), increasing the incidence 50 times over the general population. However, half of people with DS have a normal heart and thus trisomy 21 is not sufficient to cause CHD by itself. Ts65Dn mice are trisomic for orthologs of >100 Hsa21 genes, and their heart defect frequency is significantly higher than their euploid littermates. Introduction of a null allele of Creld1 into Ts65Dn increases the penetrance of heart defects significantly. However, this increase was not seen when the Creld1 null allele was introduced into Ts1Cje, a mouse that is trisomic for about two thirds of the Hsa21 orthologs that are triplicated in Ts65Dn. Among the 23 genes present in three copies in Ts65Dn but not Ts1Cje, we identified Jam2 as necessary for the increased penetrance of Creld1-mediated septal defects in Ts65Dn. Thus, overexpression of the trisomic gene, Jam2, is a necessary potentiator of the disomic genetic modifier, Creld1 No direct physical interaction between Jam2 and Creld1 was identified by several methods. Regions of Hsa21 containing genes that are risk factors of CHD have been identified, but Jam2 (and its environs) has not been linked to heart formation previously. The complexity of this interaction may be more representative of the clinical situation in people than consideration of simple single-gene models.

Genome-Wide Association Study of Down Syndrome-Associated Atrioventricular Septal Defects.

The goal of this study was to identify the contribution of common genetic variants to Down syndrome-associated atrioventricular septal defect, a severe heart abnormality. Compared with the euploid population, infants with Down syndrome, or trisomy 21, have a 2000-fold increased risk of presenting with atrioventricular septal defects. The cause of this increased risk remains elusive. Here we present data from the largest heart study conducted to date on a trisomic background by using a carefully characterized collection of individuals from extreme ends of the phenotypic spectrum. We performed a genome-wide association study using logistic regression analysis on 452 individuals with Down syndrome, consisting of 210 cases with complete atrioventricular septal defects and 242 controls with structurally normal hearts. No individual variant achieved genome-wide significance. We identified four disomic regions (1p36.3, 5p15.31, 8q22.3, and 17q22) and two trisomic regions on chromosome 21 (around PDXK and KCNJ6 genes) that merit further investigation in large replication studies. Our data show that a few common genetic variants of large effect size (odds ratio >2.0) do not account for the elevated risk of Down syndrome-associated atrioventricular septal defects. Instead, multiple variants of low-to-moderate effect sizes may contribute to this elevated risk, highlighting the complex genetic architecture of atrioventricular septal defects even in the highly susceptible Down syndrome population.