Expanding the phenotypic spectrum of NOTCH1 variants: clinical manifestations in families with congenital heart disease.

Pathogenic variants in NOTCH1 are associated with non-syndromic congenital heart disease (CHD) and Adams-Oliver syndrome (AOS). The clinical presentation of individuals with damaging NOTCH1 variants is characterized by variable expressivity and incomplete penetrance; however, data on systematic phenotypic characterization are limited. We report the genotype and phenotype of a cohort of 33 individuals (20 females, 13 males; median age 23.4 years, range 2.5-68.3 years) from 11 families with causative NOTCH1 variants (9 inherited, 2 de novo; 9 novel), ascertained from a proband with CHD. We describe the cardiac and extracardiac anomalies identified in these 33 individuals, only four of whom met criteria for AOS. The most common CHD identified was tetralogy of Fallot, though various left- and right-sided lesions and septal defects were also present. Extracardiac anomalies identified include cutis aplasia (5/33), cutaneous vascular anomalies (7/33), vascular anomalies of the central nervous system (2/10), Poland anomaly (1/33), pulmonary hypertension (2/33), and structural brain anomalies (3/14). Identification of these findings in a cardiac proband cohort supports NOTCH1-associated CHD and NOTCH1-associated AOS lying on a phenotypic continuum. Our findings also support (1) Broad indications for NOTCH1 molecular testing (any familial CHD, simplex tetralogy of Fallot or hypoplastic left heart); (2) Cascade testing in all at-risk relatives; and (3) A thorough physical exam, in addition to cardiac, brain (structural and vascular), abdominal, and ophthalmologic imaging, in all gene-positive individuals. This information is important for guiding the medical management of these individuals, particularly given the high prevalence of NOTCH1 variants in the CHD population.

Clinically Relevant Genetic Considerations for Patients With Tetralogy of Fallot.

Genetic changes affect embryogenesis, cardiac and extracardiac phenotype, development, later onset conditions, and both short- and long-term outcomes and comorbidities in the increasing population of individuals with tetralogy of Fallot (TOF). In this review, we focus on current knowledge about clinically relevant genetics for patients with TOF across the lifespan. The latest findings for TOF genetics that are pertinent to day-to-day practice and lifelong management are highlighted: morbidity/mortality, cardiac/extracardiac features, including neurodevelopmental expression, and recent changes to prenatal screening and diagnostics. Genome-wide microarray is the first-line clinical genetic test for TOF across the lifespan, detecting relevant structural changes including the most common for TOF, the 22q11.2 microdeletion. Accumulating evidence illustrates opportunities for advances in understanding and care that may arise from genetic diagnosis at any age. We also glimpse into the near future when the multigenic nature of TOF will be more fully revealed, further enhancing possibilities for preventive care. Precision medicine is nigh.

Dans la population croissante des personnes atteintes de la tétralogie de Fallot (TF), des modifications génétiques influencent l'embryogenèse, le développement, le phénotype cardiaque et extracardiaque, les complications tardives ainsi que les issues de santé et les états comorbides, à court et à long terme. Notre article de synthèse présente l'état des connaissances sur les renseignements génétiques cliniquement utiles pour les patients atteints de la TF tout au long de leur vie. Nous soulignons les découvertes récentes sur les aspects génétiques de la TF qui sont pertinentes pour la pratique clinique quotidienne et la prise en charge lors des différentes étapes de la vie : la morbidité et la mortalité, les caractéristiques cardiaques et extracardiaques (y compris l'expression neurodéveloppementale) et les changements récents touchant le dépistage et les diagnostics prénataux. La technologie de puce à ADN pour le génome entier constitue le test génétique clinique de première intention pour les personnes de tout âge atteintes de la TF, et elle permet la détection de modifications structurelles pertinentes dont celle le plus fréquemment associée à la TF, la microdélétion 22q11.2. L'utilité d'un diagnostic génétique pour améliorer la compréhension de la situation des patients de tous les âges et les soins qui leur sont offerts est de plus en plus mise en évidence. Nous entrevoyons également un avenir pas si lointain dans lequel la nature multigénique de la TF sera entièrement connue, ce qui ouvrira la voie à des soins préventifs bonifiés. La venue de la médecine de précision est imminente.

Genetic variants in DDX53 contribute to Autism Spectrum Disorder associated with the Xp22.11 locus.

Autism Spectrum Disorder (ASD) exhibits an ~4:1 male-to-female sex bias and is characterized by early-onset impairment of social/communication skills, restricted interests, and stereotyped behaviors. Disruption of the Xp22.11 locus has been associated with ASD in males. This locus includes the three-exon PTCHD1 gene, an adjacent multi-isoform long noncoding RNA (lncRNA) named PTCHD1-AS (spanning ~1Mb), and a poorly characterized single-exon RNA helicase named DDX53 that is intronic to PTCHD1-AS. While the relationship between PTCHD1/PTCHD1-AS and ASD is being studied, the role of DDX53 has not been examined, in part because there is no apparent functional murine orthologue. Through clinical testing, here, we identified 6 males and 1 female with ASD from 6 unrelated families carrying rare, predicted-damaging or loss-of-function variants in DDX53. Then, we examined databases, including the Autism Speaks MSSNG and Simons Foundation Autism Research Initiative, as well as population controls. We identified 24 additional individuals with ASD harboring rare, damaging DDX53 variations, including the same variants detected in two families from the original clinical analysis. In this extended cohort of 31 participants with ASD (28 male, 3 female), we identified 25 mostly maternally-inherited variations in DDX53, including 18 missense changes, 2 truncating variants, 2 in-frame variants, 2 deletions in the 3' UTR and 1 copy number deletion. Our findings in humans support a direct link between DDX53 and ASD, which will be important in clinical genetic testing. These same autism-related findings, coupled with the observation that a functional orthologous gene is not found in mouse, may also influence the design and interpretation of murine-modelling of ASD.