Background: Congenital heart disease (CHD) is the most common major congenital anomaly and causes significant morbidity and mortality. Epidemiologic evidence supports a role of genetics in the development of CHD. Genetic diagnoses can inform prognosis and clinical management. However, genetic testing is not standardized among individuals with CHD. We sought to develop a list of validated CHD genes using established methods and to evaluate the process of returning genetic results to research participants in a large genomic study. Methods: Two-hundred ninety-five candidate CHD genes were evaluated using a ClinGen framework. Sequence and copy number variants involving genes in the CHD gene list were analyzed in Pediatric Cardiac Genomics Consortium participants. Pathogenic/likely pathogenic results were confirmed on a new sample in a clinical laboratory improvement amendments-certified laboratory and disclosed to eligible participants. Adult probands and parents of probands who received results were asked to complete a post-disclosure survey. Results: A total of 99 genes had a strong or definitive clinical validity classification. Diagnostic yields for copy number variants and exome sequencing were 1.8% and 3.8%, respectively. Thirty-one probands completed clinical laboratory improvement amendments-confirmation and received results. Participants who completed postdisclosure surveys reported high personal utility and no decision regret after receiving genetic results. Conclusions: The application of ClinGen criteria to CHD candidate genes yielded a list that can be used to interpret clinical genetic testing for CHD. Applying this gene list to one of the largest research cohorts of CHD participants provides a lower bound for the yield of genetic testing in CHD.

We report 21 families displaying neurodevelopmental differences and multiple congenital anomalies while bearing a series of rare variants in mitogen-activated protein kinase kinase kinase kinase 4 ( MAP4K4 ). MAP4K4 has been implicated in many signaling pathways including c-Jun N-terminal and RAS kinases and is currently under investigation as a druggable target for multiple disorders. Using several zebrafish models, we demonstrate that these human variants are either loss-of-function or dominant-negative alleles and show that decreasing Map4k4 activity causes developmental defects. Furthermore, MAP4K4 can restrain hyperactive RAS signaling in early embryonic stages. Together, our data demonstrate that MAP4K4 negatively regulates RAS signaling in the early embryo and that variants identified in affected humans abrogate its function, establishing MAP4K4 as a causal locus for individuals with syndromic neurodevelopmental differences.

In children with hypertrophic cardiomyopathy (HCM), the genotype–phenotype association of abnormal electrocardiographic (ECG) features in the backdrop of gene positivity has not been well described. This study aimed to describe the abnormal ECG findings in children with HCM harboring who have genetic variants and determine the association with major adverse cardiac events (MACE). We retrospectively analyzed 81 variants-positive, phenotype-positive (V+P+), 66 variant-positive, phenotype-negative (V+P−), and 85 non-sarcomeric subjects. We analyzed ECG findings and clinical outcomes in the three groups of subjects. Repolarization abnormalities (ST and T wave changes) and pathologic Q waves were the most common abnormalities in variant and non-sarcomeric subjects. The V+P+ group showed higher occurrence of ST segment changes and T wave abnormalities compared to V+P− group. Independent predictors of MACE included ST segment changes (OR 3.54, CI 1.20–10.47, p = 0.022). T wave changes alone did not predict outcome (OR 2.13, CI 0.75–6.07, p = 0.157), but combined repolarization abnormalities (ST+T changes) were strong predictors of MACE (OR 5.84, CI 1.43–23.7, p = 0.014) than ST segment changes alone. Maximal wall z score by echocardiography was a predictor of MACE (OR 1.21, CI 1.07–1.37, p = 0.002). Despite the presence of significant myocardial hypertrophy (z score > 4.7), voltage criteria for LVH were much less predictive. In the non-sarcomeric group, RVH was significantly associated with MACE (OR 3.85, CI 1.08–13.73, p = 0.038). These abnormal ECG findings described on the platform of known genetic status and known myocardial hypertrophy may add incremental value to the diagnosis and surveillance of disease progression in children with HCM. Select ECG findings, particularly repolarization abnormalities, may serve as predictors of MACE in children.

Eukaryotic initiation factor-4A2 (EIF4A2) is an ATP-dependent RNA helicase and a member of the DEAD-box protein family that recognizes the 5' cap structure of mRNAs, allows mRNA to bind to the ribosome, and plays an important role in microRNA-regulated gene repression. Here, we report on 15 individuals from 14 families presenting with global developmental delay, intellectual disability, hypotonia, epilepsy, and structural brain anomalies, all of whom have extremely rare de novo mono-allelic or inherited bi-allelic variants in EIF4A2. Neurodegeneration was predominantly reported in individuals with bi-allelic variants. Molecular modeling predicts these variants would perturb structural interactions in key protein domains. To determine the pathogenicity of the EIF4A2 variants in vivo, we examined the mono-allelic variants in Drosophila melanogaster (fruit fly) and identified variant-specific behavioral and developmental defects. The fruit fly homolog of EIF4A2 is eIF4A, a negative regulator of decapentaplegic (dpp) signaling that regulates embryo patterning, eye and wing morphogenesis, and stem cell identity determination. Our loss-of-function (LOF) rescue assay demonstrated a pupal lethality phenotype induced by loss of eIF4A, which was fully rescued with human EIF4A2 wild-type (WT) cDNA expression. In comparison, the EIF4A2 variant cDNAs failed or incompletely rescued the lethality. Overall, our findings reveal that EIF4A2 variants cause a genetic neurodevelopmental syndrome with both LOF and gain of function as underlying mechanisms.

American Journal of Medical Genetics Part AVolume 188, Issue 10 p. 3130-3134 RESEARCH LETTER Mosaic RAI1 variant in a Smith–Magenis syndrome patient with total anomalous pulmonary venous return Yukiko Kuroda, Yukiko Kuroda Division of Human Genetics, Children's Hospital of Philadelphia, Philadelphia, Pennsylvania, USASearch for more papers by this authorAlyssa Ritter, Alyssa Ritter orcid.org/0000-0003-4735-5223 Division of Human Genetics, Children's Hospital of Philadelphia, Philadelphia, Pennsylvania, USASearch for more papers by this authorSureni V. Mullegama, Sureni V. Mullegama GeneDx, Gaithersburg, Maryland, USASearch for more papers by this authorKosuke Izumi, Corresponding Author Kosuke Izumi izumik1@chop.edu orcid.org/0000-0002-7922-7480 Division of Human Genetics, Children's Hospital of Philadelphia, Philadelphia, Pennsylvania, USA Correspondence Kosuke Izumi, Division of Human Genetics, Children's Hospital of Philadelphia, Philadelphia, PA, USA. Email: izumik1@chop.eduSearch for more papers by this author Yukiko Kuroda, Yukiko Kuroda Division of Human Genetics, Children's Hospital of Philadelphia, Philadelphia, Pennsylvania, USASearch for more papers by this authorAlyssa Ritter, Alyssa Ritter orcid.org/0000-0003-4735-5223 Division of Human Genetics, Children's Hospital of Philadelphia, Philadelphia, Pennsylvania, USASearch for more papers by this authorSureni V. Mullegama, Sureni V. Mullegama GeneDx, Gaithersburg, Maryland, USASearch for more papers by this authorKosuke Izumi, Corresponding Author Kosuke Izumi izumik1@chop.edu orcid.org/0000-0002-7922-7480 Division of Human Genetics, Children's Hospital of Philadelphia, Philadelphia, Pennsylvania, USA Correspondence Kosuke Izumi, Division of Human Genetics, Children's Hospital of Philadelphia, Philadelphia, PA, USA. Email: izumik1@chop.eduSearch for more papers by this author First published: 14 July 2022 https://doi.org/10.1002/ajmg.a.62907 Funding information: Japan Society for the Promotion of Science Read the full textAboutPDF ToolsRequest permissionExport citationAdd to favoritesTrack citation ShareShare Give accessShare full text accessShare full-text accessPlease review our Terms and Conditions of Use and check box below to share full-text version of article.I have read and accept the Wiley Online Library Terms and Conditions of UseShareable LinkUse the link below to share a full-text version of this article with your friends and colleagues. Learn more.Copy URL Share a linkShare onFacebookTwitterLinked InRedditWechat Supporting Information Filename Description ajmga62907-sup-0001-TableS1.pdfPDF document, 65.6 KB Supplemental Table 1 Supporting information. Please note: The publisher is not responsible for the content or functionality of any supporting information supplied by the authors. Any queries (other than missing content) should be directed to the corresponding author for the article. Volume188, Issue10October 2022Pages 3130-3134 RelatedInformation

BackgroundA 4-week-old Caucasian male presented with failure to thrive, grunting, irritability, and feeding difficulties.The pregnancy was complicated by intrauterine growth restriction and oligohydramnios; fetal echocardiogram was normal.He was born at term, passed his hearing test, and his newborn screening for 37 disorders was unremarkable.The family history was significant for an unexplained neonatal death of a male maternal first cousin once removed.A chest radiograph on presentation showed cardiomegaly.An echocardiogram demonstrated moderate dilation and hypertrophy of the left ventricle with a severely reduced ejection fraction (13%; normal 55%).Laboratory testing showed increased B-type natriuretic peptide (BNP) [1868.2pg/ml; reference interval (RI): 0.0-100.0pg/ml] and blood lactic acid (3.8 mmol/L; RI: 0.5-2.0mmol/L).Complete blood cell counts revealed borderline low absolute neutrophil count at 1160/mL (RI: 1108-5450/mL).Results of liver and renal function tests, plasma amino acids analysis (PAA), plasma free and total carnitine, and plasma acylcarnitine profile were normal.Urine organic acids analysis (UOA) showed borderline increases in 3methylglutaconic acid (3MGA) (25 mmol/mol creatinine; normal <22 mmol/mol creatinine) and 3-methylglutaric acid (3MG) (3.3 mmol/mol creatinine; normal

De novo variants in QRICH1 (Glutamine-rich protein 1) has recently been reported in 11 individuals with intellectual disability (ID). The function of QRICH1 is largely unknown but it is likely to play a key role in the unfolded response of endoplasmic reticulum stress through transcriptional control of proteostasis. In this study, we present 27 additional individuals and delineate the clinical and molecular spectrum of the individuals (n = 38) with QRICH1 variants. The main clinical features were mild to moderate developmental delay/ID (71%), nonspecific facial dysmorphism (92%) and hypotonia (39%). Additional findings included poor weight gain (29%), short stature (29%), autism spectrum disorder (29%), seizures (24%) and scoliosis (18%). Minor structural brain abnormalities were reported in 52% of the individuals with brain imaging. Truncating or splice variants were found in 28 individuals and 10 had missense variants. Four variants were inherited from mildly affected parents. This study confirms that heterozygous QRICH1 variants cause a neurodevelopmental disorder including short stature and expands the phenotypic spectrum to include poor weight gain, scoliosis, hypotonia, minor structural brain anomalies, and seizures. Inherited variants from mildly affected parents are reported for the first time, suggesting variable expressivity.

Purpose: This study aimed to describe the phenotypic and molecular characteristics of ARCN1-related syndrome. Methods: Patients with ARCN1 variants were identified, and clinician researchers were connected using GeneMatcher and physician referrals. Clinical histories were collected from each patient. Results: In total, we identified 14 cases of ARCN1-related syndrome, (9 pediatrics, and 5 fetal cases from 3 families). The clinical features these newly identified cases were compared to 6 previously reported cases for a total of 20 cases. Intrauterine growth restriction, micrognathia, and short stature were present in all patients. Other common features included prematurity (11/15, 73.3%), developmental delay (10/14, 71.4%), genitourinary malformations in males (6/8, 75%), and microcephaly (12/15, 80%). Novel features of ARCN1-related syndrome included transient liver dysfunction and specific glycosylation abnormalities during illness, giant cell hepatitis, hepatoblastoma, cataracts, and lethal skeletal manifestations. Developmental delay was seen in 73% of patients, but only 3 patients had intellectual disability, which is less common than previously reported. Conclusion: ARCN1-related syndrome presents with a wide clinical spectrum ranging from a severe embryonic lethal syndrome to a mild syndrome with intrauterine growth restriction, micrognathia, and short stature without intellectual disability. Patients with ARCN1-related syndrome should be monitored for liver dysfunction during illness, cataracts, and hepatoblastoma. Additional research to further define the phenotypic spectrum and possible genotype-phenotype correlations are required. (C) 2022 American College of Medical Genetics and Genomics. Published by Elsevier Inc. All rights reserved.

Sarah E. Sheppard | Ian M. Campbell | Margaret H. Harr | Nina Gold | Dong Li | Hans T. Bjornsson | Julie S. Cohen | Jill A. Fahrner | Ali Fatemi | Jacqueline R. Harris | Catherine Nowak | Cathy A. Stevens | Katheryn Grand | Margaret Au | John M. Graham Jr | Pedro A. Sanchez-Lara | Miguel Del Campo | Marilyn C. Jones | Omar Abdul-Rahman | Fowzan S. Alkuraya | Jennifer A. Bassetti | Katherine Bergstrom | Elizabeth Bhoj | Sarah Dugan | Julie D. Kaplan | Nada Derar | Karen W. Gripp | Natalie Hauser | A. Micheil Innes2 | Beth Keena | Neslida Kodra | Rebecca Miller | Beverly Nelson | Malgorzata J. Nowaczyk | Zuhair Rahbeeni | Shay Ben-Shachar | Joseph T. Shieh | Anne Slavotinek | Andrew K. Sobering | Mary-Alice Abbott | Dawn C. Allain | Louise Amlie-Wolf | Ping Yee Billie Au | Emma Bedoukian | Geoffrey Beek | James Barry | Janet Berg | Jonathan A. Bernstein | Cheryl Cytrynbaum | Brian Hon-Yin Chung | Sarah Donoghue | Naghmeh Dorrani | Alison Eaton | Josue A. Flores-Daboub | Holly Dubbs | Carolyn A. Felix | Chin-To Fong | Jasmine Lee Fong Fung | Balram Gangaram | Amy Goldstein | Rotem Greenberg | Thoa K. Ha | Joseph Hersh | Kosuke Izumi | Staci Kallish | Elijah Kravets | Pui-Yan Kwok | Rebekah K. Jobling | Amy E. Knight Johnson | Jessica Kushner | Bo Hoon Lee | Brooke Levin | Kristin Lindstrom | Kandamurugu Manickam | Rebecca Mardach | Elizabeth McCormick | D. Ross McLeod | Frank D. Mentch | Kelly Minks | Colleen Muraresku | Stanley F. Nelson | Patrizia Porazzi | Pavel N. Pichurin | Nina N. Powell-Hamilton | Zoe Powis | Alyssa Ritter | Caleb Rogers | Luis Rohena | Carey Ronspies | Audrey Schroeder | Zornitza Stark | Lois Starr | Joan Stoler | Pim Suwannarat | Milen Velinov | Rosanna Weksberg | Yael Wilnai | Neda Zadeh | Dina J. Zand | Marni J. Falk | Hakon Hakonarson | Elaine H. Zackai | Fabiola Quintero-Rivera

MYH7, encoding the myosin heavy chain sarcomeric β-myosin heavy chain, is a common cause of both hypertrophic and dilated cardiomyopathy. Additionally, families with left ventricular noncompaction cardiomyopathy (LVNC) and congenital heart disease (CHD), typically septal defects or Ebstein anomaly, have been identified to have heterozygous pathogenic variants in MHY7. One previous case of single ventricle CHD with heart failure due to a MYH7 variant has been identified. Herein, we present a single center's experience of complex CHD due to MYH7 variants. Three probands with a history of CHD, LVNC, and/or arrhythmias were identified to have MYH7 variants through multigene panel testing or exome sequencing. These three patients collectively had 12 affected family members, four with a history of Ebstein anomaly and seven with a history of LVNC. These findings suggest a wider phenotypic spectrum in MYH7-related CHD than previously understood. Further investigation into the possible role of MYH7 in CHD and mechanism of disease is necessary to fully delineate the phenotypic spectrum of MYH7-related cardiac disease. MYH7 should be considered for families with multiple individuals with complex CHD in the setting of a family history of LVNC or arrhythmias.

Background A neurodevelopmental syndrome was recently reported in four patients with SOX4 heterozygous missense variants in the high-mobility-group (HMG) DNA-binding domain. The present study aimed to consolidate clinical and genetic knowledge of this syndrome. Methods We newly identified 17 patients with SOX4 variants, predicted variant pathogenicity using in silico tests and in vitro functional assays and analysed the patients’ phenotypes. Results All variants were novel, distinct and heterozygous. Seven HMG-domain missense and five stop-gain variants were classified as pathogenic or likely pathogenic variant (L/PV) as they precluded SOX4 transcriptional activity in vitro. Five HMG-domain and non-HMG-domain missense variants were classified as of uncertain significance (VUS) due to negative results from functional tests. When known, inheritance was de novo or from a mosaic unaffected or non-mosaic affected parent for patients with L/PV, and from a non-mosaic asymptomatic or affected parent for patients with VUS. All patients had neurodevelopmental, neurological and dysmorphic features, and at least one cardiovascular, ophthalmological, musculoskeletal or other somatic anomaly. Patients with L/PV were overall more affected than patients with VUS. They resembled patients with other neurodevelopmental diseases, including the SOX11- related and Coffin-Siris (CSS) syndromes, but lacked the most specific features of CSS. Conclusion These findings consolidate evidence of a fairly non-specific neurodevelopmental syndrome due to SOX4 haploinsufficiency in neurogenesis and multiple other developmental processes.

Wiedemann-Steiner syndrome (WSS) is an autosomal dominant disorder caused by monoallelic variants in KMT2A and characterized by intellectual disability and hypertrichosis. We performed a retrospective, multicenter, observational study of 104 individuals with WSS from five continents to characterize the clinical and molecular spectrum of WSS in diverse populations, to identify physical features that may be more prevalent in White versus Black Indigenous People of Color individuals, to delineate genotype-phenotype correlations, to define developmental milestones, to describe the syndrome through adulthood, and to examine clinicians' differential diagnoses. Sixty-nine of the 82 variants (84%) observed in the study were not previously reported in the literature. Common clinical features identified in the cohort included: developmental delay or intellectual disability (97%), constipation (63.8%), failure to thrive (67.7%), feeding difficulties (66.3%), hypertrichosis cubiti (57%), short stature (57.8%), and vertebral anomalies (46.9%). The median ages at walking and first words were 20 months and 18 months, respectively. Hypotonia was associated with loss of function (LoF) variants, and seizures were associated with non-LoF variants. This study identifies genotype-phenotype correlations as well as race-facial feature associations in an ethnically diverse cohort, and accurately defines developmental trajectories, medical comorbidities, and long-term outcomes in individuals with WSS.

Truncating variants in exons 33 and 34 of the SNF2-related CREBBP activator protein (SRCAP) gene cause the neurodevelopmental disorder (NDD) Floating-Harbor syndrome (FLHS), characterized by short stature, speech delay, and facial dysmorphism. Here, we present a cohort of 33 individuals with clinical features distinct from FLHS and truncating (mostly de novo) SRCAP variants either proximal (n = 28) or distal (n = 5) to the FLHS locus. Detailed clinical characterization of the proximal SRCAP individuals identified shared characteristics: developmental delay with or without intellectual disability, behavioral and psychiatric problems, non-specific facial features, musculoskeletal issues, and hypotonia. Because FLHS is known to be associated with a unique set of DNA methylation (DNAm) changes in blood, a DNAm signature, we investigated whether there was a distinct signature associated with our affected individuals. A machine-learning model, based on the FLHS DNAm signature, negatively classified all our tested subjects. Comparing proximal variants with typically developing controls, we identified a DNAm signature distinct from the FLHS signature. Based on the DNAm and clinical data, we refer to the condition as “non-FLHS SRCAP-related NDD.” All five distal variants classified negatively using the FLHS DNAm model while two classified positively using the proximal model. This suggests divergent pathogenicity of these variants, though clinically the distal group presented with NDD, similar to the proximal SRCAP group. In summary, for SRCAP, there is a clear relationship between variant location, DNAm profile, and clinical phenotype. These results highlight the power of combined epigenetic, molecular, and clinical studies to identify and characterize genotype-epigenotype-phenotype correlations.

The NatA N-acetyltransferase complex is important for cotranslational protein modification and regulation of multiple cellular processes. The NatA complex includes the core components of NAA10, the catalytic subunit, and NAA15, the auxiliary component. Both NAA10 and NAA15 have been associated with neurodevelopmental disorders with overlapping clinical features, including variable intellectual disability, dysmorphic facial features, and, less commonly, congenital anomalies such as cleft lip or palate. Cardiac arrhythmias, including long QT syndrome, ventricular tachycardia, and ventricular fibrillation were among the first reported cardiac manifestations in patients with NAA10-related syndrome. Recently, three individuals with NAA10-related syndrome have been reported to also have hypertrophic cardiomyopathy (HCM). The general and cardiac phenotypes of NAA15-related syndrome are not as well described as NAA10-related syndrome. Congenital heart disease, including ventricular septal defects, and arrhythmias, such as ectopic atrial tachycardia, have been reported in a small proportion of patients with NAA15-related syndrome. Given the relationship between NAA10 and NAA15, we propose that HCM is also likely to occur in NAA15-related disorder. We present two patients with pediatric HCM found to have NAA15-related disorder via exome sequencing, providing the first evidence that variants in NAA15 can cause HCM.

Background Noonan Syndrome with Multiple Lentigines (NSML) and Noonan Syndrome (NS) can be difficult to differentiate clinically in early childhood. This study aims to describe characteristics of the ventricular septum that may differentiate NSML from NS. We hypothesize that the shape of the ventricular septum determined by echocardiography correlates with genotype and may distinguish patients with NSML from those with NS. Methods We analyzed data from 17 NSML and 67 NS patients. Forty normal and 30 sarcomeric hypertrophic cardiomyopathy (HCM) patients were included as controls. Septal morphology was qualitatively evaluated, and septal angle was measured quantitatively at end diastole. We recorded the presence of a ventricular septal bulge (VSB) and reviewed genetic testing results for each patient. Results The most important findings were a sigmoid septum (71%) and VSB (71%) in NSML. NSML septal angle was decreased compared to the normal and sarcomeric HCM control groups, respectively (149 ± 13 vs. 177 ± 3, p < 0.001; 149 ± 13 vs. 172 ± 7, p < 0.001). NS septal angle was similar to the controls (176 ± 6 vs. 177 ± 3, p > 0.5; 176 ± 6 vs. 172 ± 7, p > 0.5). NSML-linked pathogenic variants were associated with sigmoid septum and VSB. Conclusions These findings provide novel phenotypic evidence to clinicians that may offer incremental diagnostic value in counseling families in ambiguous NSML/NS cases. Impact Characteristics of the ventricular septum are linked to specific gene variants that cause NSML and NS. Sigmoid septum and VSB are associated with NSML. This novel echocardiographic association may help clinicians distinguish NSML from NS in ambiguous cases. Early distinction between the two may be important, as syndrome-specific therapies may become available in the near future. This study may encourage further research into genotype–phenotype associations in other forms of HCM.

American Journal of Medical Genetics Part AVolume 182, Issue 12 p. 2807-2811 ISSUE INFORMATIONFree Access Table of Contents, Volume 182A, Number 12, December 2020 First published: 20 November 2020 https://doi.org/10.1002/ajmg.a.61251AboutPDF ToolsRequest permissionExport citationAdd to favoritesTrack citation ShareShare Give accessShare full text accessShare full-text accessPlease review our Terms and Conditions of Use and check box below to share full-text version of article.I have read and accept the Wiley Online Library Terms and Conditions of UseShareable LinkUse the link below to share a full-text version of this article with your friends and colleagues. Learn more.Copy URL Share a linkShare onFacebookTwitterLinkedInRedditWechat Volume182, Issue12December 2020Pages 2807-2811 RelatedInformation