The identified variant p.(Gln77Ter) is new and absent from the genome aggregation database. It was shown that pathogenic variants in BICD2 they are extremely rare in the population, are expected to be damaging by most tools, and occur at specific hotspots within the key BICD2 functional domains [8]. Furthermore, WES did not identify any variant in any of the OMIM genes with a recognized disease association (including VPS13B gene). Despite BICD2 It is essential for the correct development of the cerebral cortex. [5] but there have been no other clinical reports of individuals with loss-of-function variants in BICD2 showing lissencephaly and cerebellar hypoplasia. However, lissencephaly and cerebellar hypoplasia are consistent with those observed after BICD2 knockdown in mice showing defects in the lamellar organization of the cerebral cortex, hippocampus, and cerebellar cortex, indicative of radial neuronal migration defects. Cell-specific inactivation of BICD2 in astrocytes and neuronal precursors revealed that radial cerebellar granule cell migration is not cell-autonomous and intrinsic to cerebellar Bergmann glial cells. [9, 10]. Therefore, we consider BICD2 be a compelling candidate gene in the context of lissencephaly and cerebellar hypoplasia. The absence of homozygous loss of function. BICD2 variants in healthy family members supports the clinical relevance of BICD2.
Recently, biallelic variant c.731 T > C p.(Leu244Pro) in BICD2 was described in a girl with an abnormal turning pattern in the fronto-temporo-parietal regions [6] (Table 1). The girl also showed a moderate intellectual disability and features similar to those of Cohen. [6]. In comparison, our patient presented with congenital microcephaly, profound retardation, seizures, lissencephaly, and cerebellar hypoplasia. Unlike the patient with Cohen-like features, our patient showed spasticity and developed contracture deformities and no neutropenia. Interestingly, a heterozygous nonsense variant c.2080 C>T was reported, p. (Arg694Cys) in two unrelated patients with mild perisylvian polymicrogyria and mild hypoplasia of the cerebellar vermis. [4]. Also, a BICD2 A nonsense variation p.(Lys775Ter) was identified in a child with lissencephaly and subcortical band heterotopia [5]. These heterozygous variants are found within the highly conserved CC3 domain of BICD2 (Table 1). However, heterozygous missense variants within the CC1 domain were not associated with cortical developmental abnormalities, but even showed a milder course of SMALED2A and a higher frequency of foot deformities. [8]. Indeed, a larger cohort is required to draw conclusions regarding genotype-phenotype correlations.
The lissencephaly and cerebellar hypoplasia noted in our patient appeared similar to those with LIS1 variants. This is not surprising since LIS1 interacts with the dynein/dynactin complex and BICD2 to recruit cellular structures [11]. Meanwhile, these brain MRI features may overlap with CLOCK-Phenotype of mutated patients. However, the cortical migration defect was more severe in our patient than in CLOCK-mutated patients. In addition, our patient had mild cerebellar hypoplasia unlike CLOCK-mutated patients who had profoundly hypoplastic and dysplastic cerebellum with no identifiable folia [12].
Our study provides valuable findings on human developmental brain malformation disorders associated with definitive loss-of-function variants in BICD2.