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The expanding clinical phenotype of germline ABL1 ‐associated congenital heart defects and skeletal malformations syndrome
Author(s) -
Chen ChunAn,
Crutcher Emeline,
Gill Harinder,
Nelson Tanya N.,
Robak Laurie A.,
Jongmans Marjolijn C. J.,
Pfundt Rolph,
Prasad Chitra,
Berard Roberta A.,
Fannemel Madeleine,
Frengen Eirik,
Misceo Doriana,
Ramsey Keri,
Yang Yaping,
Schaaf Christian P.,
Wang Xia
Publication year - 2020
Publication title -
human mutation
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.981
H-Index - 162
eISSN - 1098-1004
pISSN - 1059-7794
DOI - 10.1002/humu.24075
Subject(s) - biology , germline , missense mutation , failure to thrive , phenotype , hypoplasia , germline mutation , genetics , medicine , mutation , anatomy , gene
Congenital heart defects and skeletal malformations syndrome (CHDSKM) is a rare autosomal dominant disorder characterized by congenital heart disease, skeletal abnormalities, and failure to thrive. CHDSKM is caused by germline mutations in ABL1 . To date, three variants have been in association with CHDSKM. In this study, we describe three de novo missense variants, c.407C>T (p.Thr136Met), c.746C>T (p.Pro249Leu), and c.1573G>A (p.Val525Met), and one recurrent variant, c.1066G>A (p.Ala356Thr), in six patients, thereby expanding the phenotypic spectrum of CHDSKM to include hearing impairment, lipodystrophy‐like features, renal hypoplasia, and distinct ocular abnormalities. Functional investigation of the three novel variants showed an increased ABL1 kinase activity. The cardiac findings in additional patients with p.Ala356Thr contribute to the accumulating evidence that patients carrying either one of the recurrent variants, p.Tyr245Cys and p.Ala356Thr, have a high incidence of cardiac abnormalities. The phenotypic expansion has implications for the clinical diagnosis of CHDSKM in patients with germline ABL1 variants.