Low‐grade parental gonosomal mosaicism in CHD2 siblings with Smith–Magenis‐like syndrome

Author:

Cogliati Francesca1ORCID,Straniero Letizia23ORCID,Rimoldi Valeria23ORCID,Masciadri Maura1ORCID,Perego Sara1ORCID,Rinaldi Berardo4ORCID,Milani Donatella5ORCID,Gentilini Davide67ORCID,Larizza Lidia1ORCID,Asselta Rosanna23ORCID,Russo Silvia1ORCID,Bedeschi Maria Francesca4ORCID

Affiliation:

1. Research Laboratory of Medical Cytogenetics and Molecular Genetics IRCCS Istituto Auxologico Italiano Milan Italy

2. Department of Biomedical Sciences Humanitas University Milan Italy

3. IRCCS Humanitas Research Hospital Milan Italy

4. Fondazione IRCCS Ca’ Granda Ospedale Maggiore Policlinico Medical Genetics Unit Milan Italy

5. Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico Milan Italy

6. Bioinformatics and Statistical Genomics Unit IRCCS Istituto Auxologico Italiano Cusano Milanino Italy

7. Department of Brain and Behavioral Sciences University of Pavia Pavia Italy

Abstract

AbstractLoss‐of‐function CHD2 (chromodomain helicase DNA‐binding protein 2) mutations are associated with a spectrum of neurodevelopmental disorders often including early‐onset generalized seizures, photosensitivity, and epileptic encephalopathies. Patients show psychomotor delay/intellectual disability (ID), autistic features, and behavior disorders, such as aggression and impulsivity. Most reported cases are sporadic with description of germline mosaicism only in two families. We detect the first case of parental gonosomal CHD2 mosaicism disclosed by two brothers showing mild ID, born to healthy parents. The eldest brother has a history of drug‐controlled generalized tonic–clonic seizures and displays sleep disorder and aggressive behavior suggestive of Smith–Magenis syndrome (SMS). Analysis of brothers’ DNAs by next‐generation sequencing (NGS) custom gene panel for pediatric epilepsy and/or ID disclosed in both the same pathogenic CHD2 variant. Additional NGS experiment on genomic DNA from parents’ peripheral blood and from buccal swab raised the suspicion of low‐grade gonosomal mosaicism in the unaffected mother subsequently confirmed by digital polymerase chain reaction (dPCR). This report underlines as worthwhile CHD2 screening in individuals presenting ID/developmental delay, with/without epilepsy, and behavior and sleep disorders suggestive of SMS. Detecting a CHD2 variant should prime testing probands' parents by NGS coupled to dPCR on different tissues to exclude/confirm gonosomal mosaicism and define the recurrence risk.

Publisher

Wiley

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