A homozygous loss-of-function variant in BICD2 is associated with lissencephaly and cerebellar hypoplasia

Abstract

Developmental brain malformations are rare but are increasingly reported features of BICD2-related disorders. Here, we report a 2-year old boy with microcephaly, profound delay and partial seizures. His brain MRI showed lissencephaly, hypogenesis of corpus callosum, dysplastic hipocampus and cerebellar hypoplasia. Whole-exome sequencing identified a novel homozygous likely pathogenic variant in the BICD2 gene, c.229 C > T p.(Gln77Ter). This is the first report of lissencephaly and cerebellar hypoplasia seen in a patient with homozygous loss-of-function variant in BICD2 that recapitulated the animal model. Our report supports that BICD2 should be considered in the differential diagnosis for patients with lissencephaly and cerebellar hypoplasia Additional clinical features of BICD2 are likely to emerge with the identification of additional patients.

Expanding association between BICD2 variants and brain malformations and associated lissencephaly

“…Notably, microcephaly was observed in all BICD2 -related lissencephaly cases unlike other BICD2 -related brain malformations, while arthrogryposis commonly found in BICD2 -related SMALED2A/2B patients was rare in lissencephaly patients. Our patient exhibited microcephaly and lissencephaly, consistent with previous studies [ 4 , 9 , 10 ]. We observed developmental regression in our patient, a novel occurrence in BICD2 -related disease patients during long-term follow-up until age 7 ( Table 1 ).…”

“…Our patient exhibited microcephaly and lissencephaly, consistent with previous studies. 4,9,10) We observed developmental regression in our patient, a novel occurrence in BICD2-related disease patients during long-term follow-up until age 7 (Table 1). We suspect it may result from refractory seizures not reported before.…”

“…Variants in Bicaudal D2 Drosophila homolog 2 ( BICD2 ) were known to be associated with autosomal dominant lower extremity-predominant spinal muscular atrophy 2 (SMALED2A/2B; Online Mendelian Inheritance in Man [OMIM]) [ 2 , 3 ]. After a recent study demonstrating loss of BICD2 function are associated with brain malformations in human [ 4 ], 9 patients with BICD2 variants were reported to be associated with brain malformations [ 5 - 10 ]. However, only a few patients have been reported to exhibit lissencephaly in brain imaging, and as such, this phenotype has not yet been added to the OMIM database.…”

“…2,3) After a recent study demonstrating loss of BICD2 function are associated with brain malformations in human, 4) 9 patients with BICD2 variants were reported to be associated with brain malformations. [5][6][7][8][9][10] However, only a few patients have been reported to exhibit lissencephaly in brain imaging, and as such, this phenotype has not yet been added to the OMIM database. We report a case of Korean female patient with novel heterozygous BICD2 variant with developmental regression and lissencephaly, expanding neurologic phenotypic spectrum of BICD2-associated dis ease.…”