Expanding the phenotype of ASXL3‐related syndrome: A comprehensive description of 45 unpublished individuals with inherited and de novo pathogenic variants in ASXL3

Abstract

The study aimed at widening the clinical and genetic spectrum of ASXL3‐related syndrome, a neurodevelopmental disorder, caused by truncating variants in the ASXL3 gene. In this international collaborative study, we have undertaken a detailed clinical and molecular analysis of 45 previously unpublished individuals with ASXL3‐related syndrome, as well as a review of all previously published individuals. We have reviewed the rather limited functional characterization of pathogenic variants in ASXL3 and discuss current understanding of the consequences of the different ASXL3 variants. In this comprehensive analysis of ASXL3‐related syndrome, we define its natural history and clinical evolution occurring with age. We report familial ASXL3 pathogenic variants, characterize the phenotype in mildly affected individuals and discuss nonpenetrance. We also discuss the role of missense variants in ASXL3. We delineate a variable but consistent phenotype. The most characteristic features are neurodevelopmental delay with consistently limited speech, significant neuro‐behavioral issues, hypotonia, and feeding difficulties. Distinctive features include downslanting palpebral fissures, hypertelorism, tubular nose with a prominent nasal bridge, and low‐hanging columella. The presented data will inform clinical management of individuals with ASXL3‐related syndrome and improve interpretation of new ASXL3 sequence variants.

Report of two children with global developmental delay in association with de novo TLK2 variant and literature review

“…This shows that population prevalence of both heterozygous recessive or dominant TLK2 gene mutations may be higher than currently recognized. A similar phenomenon can be seen in other known inherited heterozygous gene variants, where heterozygous parents of a proband are either clinically unaffected or have very mild disease, such as ASXL3 (Schirwani et al, 2021) and in several copy number variants such as 22q11.2 microdeletion syndrome (Kylat, 2018).…”

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

“…The intrafamilial variability evident in Family 2 and 3 along with previous reports of phenotypic variability in patients with the same ASXL3 gene variant (Schirwani et al, 2021), underscores the difficulty in establishing clear genotype-phenotype correlation in this disorder (Table 1). In Family 2, the mother and both affected siblings all have significantly different developmental, intellectual and educational profiles; ranging from mild ID in mainstream schooling, to severe ID requiring specialist schooling.…”

ASXL3 De Novo Variant-Related Neurodevelopmental Disorder Presenting as Dystonic Cerebral Palsy

“…8 Nevertheless, we stress that it is not possible to accurately infer the frequency of specific phenotypic aspects of a disorder by conducting single-case analysis and retrospective literature review. While a recent larger BRPS cohort study has not discussed features of dystonia or cerebral palsy, 9 we highlight the need for future prospective investigations, also incorporating movement-disorder expert assessment and targeted rating scales to clarify the true prevalence of different motor symptoms in ASXL3 -associated disease.…”