“Low-level parental somatic mosaicism detected by exome sequencing in cohort of patients with neurodevelopmental disorders

Kód výsledku v IS VaVaI

<a href="https://www.isvavai.cz/riv?ss=detail&h=RIV%2F00216224%3A14310%2F22%3A00126521" target="_blank" >RIV/00216224:14310/22:00126521 - isvavai.cz</a>

Výsledek na webu

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DOI - Digital Object Identifier

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Jazyk výsledku

angličtina

Název v původním jazyce

“Low-level parental somatic mosaicism detected by exome sequencing in cohort of patients with neurodevelopmental disorders

Popis výsledku v původním jazyce

Low-level somatic mosaicism leading to neurodevelopmental disorders (NDDs) and autism is more prevalent than previously thought. Due to limitations in its detection by routine molecular techniques, e.g. chromosomal microarrays or Sanger sequencing, detected single-nucleotide variants (SNVs) or small indel variants are often misinterpreted as de novo in the affected offspring. However, low-level somatic mosaicism in parents may significantly increase the risk of passing pathogenic variants to the offspring. We present our experience with exome sequencing as an effective approach for the detection of low-level parental somatic mosaicism for clinically relevant SNVs in patients with NDDs. Our study included 45 families (trios or quatros) of infants with NDDs examined using the commercial kit Human Core Exome (Twist Biosciences) and Illumina NovaSeq 6000. Using a customized bioinformatic pipeline, we detected SNVs or indel variants classified as pathogenic or likely pathogenic in 18/48 children (37.5%). Two SNVs classified as pathogenic in probands were detected in parental blood samples as low-level mosaicism (10-15%), both in fathers. The father of patient with c.7059G&gt;C variant in DYNC1H gene exhibited learning disabilities, a phenotype possibly related to the mosaic change. The father harbouring mosaic variant c.911dup in CTNNB1 gene was clinically unaffected. Our data demonstrate the importance of considering the possibility of parental mosaicism whenever exome sequencing is performed for precise genetic counselling. Supported by Ministry of Health of the Czech Republic, grant nr. NU20-07-00145. All rights reserved.

Název v anglickém jazyce

“Low-level parental somatic mosaicism detected by exome sequencing in cohort of patients with neurodevelopmental disorders

Popis výsledku anglicky

Low-level somatic mosaicism leading to neurodevelopmental disorders (NDDs) and autism is more prevalent than previously thought. Due to limitations in its detection by routine molecular techniques, e.g. chromosomal microarrays or Sanger sequencing, detected single-nucleotide variants (SNVs) or small indel variants are often misinterpreted as de novo in the affected offspring. However, low-level somatic mosaicism in parents may significantly increase the risk of passing pathogenic variants to the offspring. We present our experience with exome sequencing as an effective approach for the detection of low-level parental somatic mosaicism for clinically relevant SNVs in patients with NDDs. Our study included 45 families (trios or quatros) of infants with NDDs examined using the commercial kit Human Core Exome (Twist Biosciences) and Illumina NovaSeq 6000. Using a customized bioinformatic pipeline, we detected SNVs or indel variants classified as pathogenic or likely pathogenic in 18/48 children (37.5%). Two SNVs classified as pathogenic in probands were detected in parental blood samples as low-level mosaicism (10-15%), both in fathers. The father of patient with c.7059G&gt;C variant in DYNC1H gene exhibited learning disabilities, a phenotype possibly related to the mosaic change. The father harbouring mosaic variant c.911dup in CTNNB1 gene was clinically unaffected. Our data demonstrate the importance of considering the possibility of parental mosaicism whenever exome sequencing is performed for precise genetic counselling. Supported by Ministry of Health of the Czech Republic, grant nr. NU20-07-00145. All rights reserved.

Druh

O - Ostatní výsledky

CEP obor

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OECD FORD obor

10603 - Genetics and heredity (medical genetics to be 3)

Projekt

<a href="/cs/project/NU20-07-00145" target="_blank" >NU20-07-00145: Úloha patogenních genetických variant detekovaných pomocí exomového sekvenování v etiologii dětských neurovývojových onemocnění</a><br>

Návaznosti

P - Projekt vyzkumu a vyvoje financovany z verejnych zdroju (s odkazem do CEP)

Rok uplatnění

2022

Kód důvěrnosti údajů

S - Úplné a pravdivé údaje o projektu nepodléhají ochraně podle zvláštních právních předpisů