The expanding clinical phenotype of germline ABL1-associated congenital heart defects and skeletal malformations syndrome

Chun-An Chen; Emeline Crutcher; Harinder Gill; Tanya N Nelson; Laurie A Robak; Marjolijn C J Jongmans; Rolph Pfundt; Chitra Prasad; Roberta A Berard; Madeleine Fannemel; Eirik Frengen; Doriana Misceo; Keri Ramsey; Yaping Yang; Christian P Schaaf; Xia Wang

doi:10.1002/humu.24075

The expanding clinical phenotype of germline ABL1-associated congenital heart defects and skeletal malformations syndrome

Hum Mutat. 2020 Oct;41(10):1738-1744. doi: 10.1002/humu.24075. Epub 2020 Jul 19.

Authors

Chun-An Chen^{1

2}, Emeline Crutcher^{1

2

3}, Harinder Gill^{4

5}, Tanya N Nelson^{4

6

7}, Laurie A Robak¹, Marjolijn C J Jongmans⁸, Rolph Pfundt⁸, Chitra Prasad^{9

10}, Roberta A Berard^{9

10

11}, Madeleine Fannemel¹², Eirik Frengen¹³, Doriana Misceo¹³, Keri Ramsey¹⁴, Yaping Yang^{1

15

16}, Christian P Schaaf^{1

2

17}, Xia Wang^{1

15

16}

Affiliations

¹ Department of Human and Molecular Genetics, Baylor College of Medicine, Houston, Texas.
² Jan and Dan Duncan Neurological Research Institute, Texas Children's Hospital, Houston, Texas.
³ Development, Disease Models, and Therapeutics Graduate Program, Baylor College of Medicine, Houston, Texas.
⁴ Department of Medical Genetics, University of British Columbia, Vancouver, British Columbia, Canada.
⁵ Provincial Medical Genetics Program, BC Women's Hospital and Health Centre, Vancouver, British Columbia, Canada.
⁶ Department of Pathology and Laboratory Medicine, BC Children's Hospital, Vancouver, British Columbia, Canada.
⁷ Department of Pathology and Laboratory Medicine, University of British Columbia, Vancouver, British Columbia, Canada.
⁸ Department of Human Genetics, Radboud University Medical Center and Radboud Institute for Molecular Life Sciences, Nijmegen, The Netherlands.
⁹ Genetics and Development, Children's Health Research Institute, London, Ontario, Canada.
¹⁰ Department of Pediatrics, Schulich School of Medicine and Dentistry, Western University, London, Ontario, Canada.
¹¹ Division of Rheumatology, Children's Hospital, London, Ontario, Canada.
¹² Department of Medical Genetics, Rikshospitalet, Oslo University Hospital, Oslo, Norway.
¹³ Department of Medical Genetics, Oslo University Hospital and University of Oslo, Oslo, Norway.
¹⁴ Center for Rare Childhood Disorders, Translational Genomics Research Institute, Phoenix, Arizona.
¹⁵ Baylor Genetics, Houston, Texas.
¹⁶ AiLife Diagnostics, Pearland, Texas.
¹⁷ Institute of Human Genetics, Heidelberg University, Heidelberg, Germany.

PMID: 32643838
DOI: 10.1002/humu.24075

Abstract

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.

Keywords: CHDSKM; congenital heart defects; hearing impairment; renal hypoplasia; skeletal malformations.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Abnormalities, Multiple* / diagnosis
Abnormalities, Multiple* / genetics
Germ Cells
Heart Defects, Congenital* / genetics
Humans
Phenotype
Syndrome