Genetic landscape of Rett syndrome-like phenotypes revealed by whole exome sequencing

Abstract

BackgroundRett syndrome (RTT) is a characteristic neurological disease presenting with regressive loss of neurodevelopmental milestones. Typical RTT is generally caused by abnormality of methyl-CpG binding protein 2 (MECP2). Our objective to investigate the genetic landscape of MECP2-negative typical/atypical RTT and RTT-like phenotypes using whole exome sequencing (WES).MethodsWe performed WES on 77 MECP2-negative patients either with typical RTT (n=11), atypical RTT (n=22) or RTT-like phenotypes (n=44) incompatible with the RTT criteria.ResultsPathogenic or likely pathogenic single-nucleotide variants in 28 known genes were found in 39 of 77 (50.6%) patients. WES-based CNV analysis revealed pathogenic deletions involving six known genes (including MECP2) in 8 of 77 (10.4%) patients. Overall, diagnostic yield was 47 of 77 (61.0 %). Furthermore, strong candidate variants were found in four novel genes: a de novo variant in each of ATPase H+ transporting V0 subunit A1 (ATP6V0A1), ubiquitin-specific peptidase 8 (USP8) and microtubule-associated serine/threonine kinase 3 (MAST3), as well as biallelic variants in nuclear receptor corepressor 2 (NCOR2).ConclusionsOur study provides a new landscape including additional genetic variants contributing to RTT-like phenotypes, highlighting the importance of comprehensive genetic analysis.

Clinical exome sequencing as the first-tier test for diagnosing developmental disorders covering both CNV and SNV: a Chinese cohort

“…Conventional exome sequencing (ES) mainly focuses on the detection of SNVs and indels. However, with the increased sensitivity and accuracy of detecting CNV through ES data, this method can now be used in clinical scenarios 5–9. Compared with traditional methodologies, CNV detection based on ES offers a more flexible resolution for large-scale parallel assessment.…”

“…In addition to large CNVs, small CNVs of exon-level deletions can also be identified with high-depth next-generation sequencing (NGS) data10–12; these deletions might not be detected in low-resolution microarray tests. The American College of Medical Genetics and Genomics (ACMG) has offered guidelines for CNV and SNV interpretation,13–15 and several studies based on ES data have been published for genetic diagnoses2 8 9 16–21; however, there are still some limitations: (1) traditional pipelines have merely been deployed on either SNV or CNV analysis, leaving the other part not thoroughly evaluated; (2) ES for CNV diagnosis was performed after microarray test screening, making the performance of absolute ES-based diagnosis unclear; and (3) studies of heterogeneous disorders or with small sample sizes, resulted in insufficient guidance for clinical application and poor expectations of diagnostic yield in particular disorders.…”

Expansion of the phenotypic spectrum of de novo missense variants in kinesin family member 1A ( KIF1A )

“…Due to the considerable overlap of clinical symptoms of RTT patients, especially those who are MECP2 ‐mutation‐negative, with other neurodevelopment disorders, it can be challenging to establish a precise genetic diagnosis. However, recent advances in next‐generation sequencing (NGS) have identified pathogenic variants in a growing list of genes known to cause intellectual disability, severe epilepsy and/or autistic behaviors where some individuals appear to have an RTT‐like clinical picture, thus providing a definitive genetic diagnosis for patients and “closure” for affected families (Cogliati et al, 2019; Henriksen, Ravn, Paus, von Tetzchner, & Skjeldal, 2018; Iwama et al, 2019; Schonewolf‐Greulich et al, 2019; Vidal et al, 2019; Yoo et al, 2017).…”

Nuclear Receptor Coactivators (NCOAs) and Corepressors (NCORs) in the Brain

“…A heterozygous NCOR2 missense variant [c.1940C > T (S647L)] is found in atypical Rett syndrome patients ( 80 ). A patient with microcephaly and intelligence disability carries compound heterozygous variants [c.3983A > G (E1328G)] and [c.1399G >A (V467I)] of NCOR2 ( 81 ).…”