Familial Bainbridge-Ropers syndrome: Report of familial ASXL3 inheritance and a milder phenotype

Schaida Schirwani; Emily Woods; David A Koolen; Charlotte W Ockeloen; Sally Ann Lynch; Karl Kavanagh; John M Graham Jr; Katheryn Grand; Tyler Mark Pierson; Jeffrey M Chung; Meena Balasubramanian

doi:10.1002/ajmg.a.62981

Familial Bainbridge-Ropers syndrome: Report of familial ASXL3 inheritance and a milder phenotype

Am J Med Genet A. 2023 Jan;191(1):29-36. doi: 10.1002/ajmg.a.62981. Epub 2022 Sep 29.

Authors

Schaida Schirwani^{1

2}, Emily Woods², David A Koolen³, Charlotte W Ockeloen³, Sally Ann Lynch⁴, Karl Kavanagh⁴, John M Graham Jr⁵, Katheryn Grand⁵, Tyler Mark Pierson^{6

7

8

9}, Jeffrey M Chung⁷, Meena Balasubramanian^{1

2}

Affiliations

¹ Department of Oncology & Metabolism, University of Sheffield, Sheffield, UK.
² Sheffield Clinical Genetics Service, Sheffield Children's NHS Foundation Trust, Sheffield, UK.
³ Department of Human Genetics, Donders Institute for Brain, Cognition and Behavior, Radboud University Medical Center, Nijmegen, Netherlands.
⁴ Department of Clinical Genetics, Children's Health Ireland, Dublin, Ireland.
⁵ Division of Medical Genetics, Department of Pediatrics, Cedars-Sinai Medical Center, Los Angeles, California, USA.
⁶ Department of Pediatrics, Cedars-Sinai Medical Center, Los Angeles, California, USA.
⁷ Department of Neurology, Cedars-Sinai Medical Center, Los Angeles, California, USA.
⁸ Cedars-Sinai Center for the Undiagnosed Patient, Cedars-Sinai Medical Center, Los Angeles, California, USA.
⁹ Board of Governors Regenerative Medicine Institute, Cedars-Sinai Medical Center, Los Angeles, California, USA.

Abstract

De novo truncating and splicing pathogenic variants in the Additional Sex Combs-Like 3 (ASXL3) gene are known to cause neurodevelopmental delay, intellectual disability, behavioral difficulties, hypotonia, feeding problems and characteristic facial features. We previously reported 45 patients with ASXL3-related disorder including three individuals with a familial variant. Here we report the detailed clinical and molecular characteristics of these three families with inherited ASXL3-related disorder. First, a father and son with c.2791_2792del p.Gln931fs pathogenic variant. The second, a mother, daughter and son with c.4534C > T, p.Gln1512Ter pathogenic variant. The third, a mother and her daughter with c.4441dup, p.Leu1481fs maternally inherited pathogenic variant. This report demonstrates intrafamilial phenotypic heterogeneity and confirms heritability of ASXL3-related disorder.

Keywords: ASXL3; Bainbridge-Ropers syndrome; developmental delay.

MeSH terms

Abnormalities, Multiple*
Child
Developmental Disabilities* / genetics
Female
Humans
Intellectual Disability* / diagnosis
Intellectual Disability* / genetics
Phenotype
Syndrome
Transcription Factors / genetics

Substances

ASXL3 protein, human
Transcription Factors