Parental Somatic Mosaicism Uncovers Inheritance of an Apparently De Novo GFAP Mutation

Alice Grossi; Federico Morelli; Marco Di Duca; Francesco Caroli; Isabella Moroni; Davide Tonduti; Tiziana Bachetti; Isabella Ceccherini

doi:10.3389/fgene.2021.744068

Parental Somatic Mosaicism Uncovers Inheritance of an Apparently De Novo GFAP Mutation

Front Genet. 2021 Dec 7:12:744068. doi: 10.3389/fgene.2021.744068. eCollection 2021.

Authors

Alice Grossi¹, Federico Morelli¹, Marco Di Duca², Francesco Caroli¹, Isabella Moroni³, Davide Tonduti⁴, Tiziana Bachetti^{1

5}, Isabella Ceccherini¹

Affiliations

¹ UOSD Laboratory of Genetics and Genomics of Rare Diseases, IRCCS Istituto Giannina Gaslini, Genoa, Italy.
² Laboratory of Molecular Nephrology, IRCCS Istituto Giannina Gaslini, Genoa, Italy.
³ Department of Pediatric Neurosciences, Fondazione IRCCS Istituto Neurologico Carlo Besta, Milan, Italy.
⁴ Unit of Pediatric Neurology - C.O.A.L.A (Center for Diagnosis and Treatment of Leukodystrophies), V. Buzzi Children's Hospital, Milan, Italy.
⁵ Laboratory of Developmental Neuro-Biology, DISTAV, University of Genoa, Genoa, Italy.

Abstract

Alexander disease is a leukodystrophy caused by heterozygous mutations of GFAP gene. Recurrence in siblings from healthy parents provides a confirmation to the transmission of variants through germinal mosaicism. With the use of DNA isolated from peripheral blood, next-generation sequencing (NGS) of GFAP locus was performed with deep coverage (≥500×) in 11 probands and their parents (trios) with probands heterozygous for apparently de novo GFAP mutations. Indeed, one parent had somatic mosaicism, estimated in the range of 8.9%-16%, for the mutant allele transmitted to the affected sibling. Parental germline mosaicism deserves attention, as it is critical in assessing the risk of recurrence in families with Alexander disease.

Keywords: Alexander disease; DNA sequence analysis; GFAP gene; central nervous system diseases; genetic counseling; germline mosaicism; human genetics; somatic mosaicism.