Novel noncanonical splice site variant causes mild CHD7-related disorder with variable intrafamilial expressivity.

Autor: Boschann F; Institute of Medical Genetics and Human Genetics, Charité - Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin and Humboldt-Universität zu Berlin, Berlin, Germany.; Berlin Institute of Health at Charité - Universitätsmedizin Berlin, BIH Biomedical Innovation Academy, BIH Charité Clinician Scientist Program, Berlin, Germany., Kosmehl S; Department of Otorhinolaryngology, Helios Hospital Berlin-Buch, Berlin, Germany., Bloching M; Department of Otorhinolaryngology, Helios Hospital Berlin-Buch, Berlin, Germany., Grünhagen J; Labor Berlin Charité Vivantes GmbH-Corporate Member of Institute for Medical Genetics and Human Genetics, Charité-Universitätsmedizin Berlin, Berlin, Germany., Hildebrand G; Institute of Medical Genetics and Human Genetics, Charité - Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin and Humboldt-Universität zu Berlin, Berlin, Germany., Horn D; Institute of Medical Genetics and Human Genetics, Charité - Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin and Humboldt-Universität zu Berlin, Berlin, Germany., Lyutenski S; Department of Otorhinolaryngology, Helios Hospital Berlin-Buch, Berlin, Germany.
Jazyk: angličtina
Zdroj: American journal of medical genetics. Part A [Am J Med Genet A] 2023 Apr; Vol. 191 (4), pp. 1128-1132. Date of Electronic Publication: 2023 Jan 27.
DOI: 10.1002/ajmg.a.63122
Abstrakt: The clinical diagnosis criteria for CHARGE syndrome have been revised several times in the last 25 years. Variable expressivity and reduced penetrance are known, particularly in mild and familial cases. Therefore, it has been proposed to include the detection of a pathogenic CHD7 variant as a major diagnostic criterion. However, intronic variants not located at the canonical splice site are still underrepresented in mutation databases, often because functional analysis is not performed in the diagnostic setting. Here, we report a two-generation family that did not meet the criteria for CHARGE syndrome, until the molecular findings were taken into account. By exome sequencing, we detected an intronic variant in a male individual, who presented with unilateral external ear malformation, bilateral semicircular canal aplasia, polydactyly, vertebral body fusion and a heart defect. The variant was inherited by his mother, who also had bilateral semicircular canal aplasia additionally to unilateral sensorineural hearing impairment, unilateral mandibular palpebral synkinesia, orofacial cleft, and dysphagia. Using RNA studies, we were able to demonstrate that aberrant splicing occurs at an upstream cryptic splice acceptor site, resulting in a frameshift and premature stop of translation. Our data show causality of the noncanonical intronic CHD7 variant and end the diagnostic odyssey of this unsolved phenotype of the family.
(© 2023 The Authors. American Journal of Medical Genetics Part A published by Wiley Periodicals LLC.)
Databáze: MEDLINE
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