Expanding the clinical phenotype associated with an ASXL1 pathogenic variant causing a novel neuromuscular disorder...

Germline pathogenic variants in the Additional Sex Combs-Like 1 (ASXL1) gene are associated with the neurodevelopmental Bohring-Opitz syndrome and cancers like Wilms' tumours. Bohring-Opitz syndrome is a phenotypically heterogeneous condition characterised by feeding difficulties, syndromic facial abnormalities, abnormal posturing and developmental delays, and it has only been reported in infant/adolescent patients. There are no reported neuromuscular phenotypes associated with ASXL1.

A 71-year-old male proband exhibited congenital facial, extraocular, proximal upper limb and generalised/distal lower limb muscle weakness/wasting. This was associated with dysphagia, childhood motor developmental delay, bilateral upper limb tremor and bilateral pes cavus. He demonstrated some features of Bohring-Opitz syndrome including feeding difficulties, microcephaly, micrognathia and anteverted nares but lacked the characteristic posturing. Muscle imaging demonstrated symmetrical lower limb atrophy. His adult age diagnosis is unique among ASXL1-associated conditions. A genetic diagnosis of the ASXL1 variant (c.1210C>T; p.Arg404Ter) was achieved through phenotype-driven genetic neurodevelopmental panel testing given some overlap with neurodevelopmental patients following unsuccessful initial genetic sequencing.

This expands the phenotype of ASXL1 pathogenic variants with a novel and distinct neuromuscular presentation. This case demonstrates the importance of thorough and accurate phenotype for unusual presentations, as this diagnosis was missed through routine genetic testing.