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

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.

ASXL3‐related disorder: Molecular phenotyping and comprehensive review providing insights into disease mechanism

“…Consideration of vagal nerve stimulator (VNS), ketotic diet or focal resection has been suggested for patients with intractable medication‐resistant epilepsy. One individual described by Schirwani et al 53 was non‐responsive to VNS insertion.…”

“…Despite the overlapping Marfanoid features, there have been no reports of children with a dilated aorta, as is associated with Marfan syndrome and other connective tissue disorders. One child was found to have a subclavian artery aneurysm 53 …”

“…Abnormal EEG reports included multifocal epileptiform activity including sharp-waves, variable background slowing, posterior rhythmic delta activity, diffusely increased beta waves. 38,47,48 53 was non-responsive to VNS insertion.…”

“…Individuals with variants c.4534C>T p.(Gln1512*) and c.2791_2792del p.(Gln931fs) were presumed to be inherited, as parents had a consistent ASXL3-related disorder phenotype. 53 There have been genetically confirmed inherited cases. Of these, a c.4441dup p.(Leu1481fs) variant was seen in a clinically severely affected daughter and clinically unaffected mother.…”

“…In a few individuals, inheritance was not genetically confirmed (Table A1 in Appendix). Individuals with variants c.4534C>T p.(Gln1512*) and c.2791_2792del p.(Gln931fs) were presumed to be inherited, as parents had a consistent ASXL3‐related disorder phenotype 53 . There have been genetically confirmed inherited cases.…”