The prevalence of BSCL2-related dHMN is largely unknown and families have been described in both Caucasian and Asian populations. As mentioned, BSCL2-related dHMN pathogenic variants are inherited in an autosomal dominant manner. Single-gene testing can be performed in cases were a typical Silver Syndrome phenotype is present. For patients with a more subtle clinical expression, such as classic dHMN, a multigene panel is less time consuming and most likely to identify the genetic cause at a reasonable cost.
The p.Asn88Ser and p.Ser90Leu mutations account for the majority of BSCL2 patients, whilst the p.Ser90Trp and p.Arg96His mutations have been less frequently documented.
The p.Asn88Ser missense mutation is located in exon 3 of the BSCL2 gene on chromosome 11q13. BSCL2 encodes the integral membrane protein named Seipin, with different putative functions ranging from phospholipid metabolism to fat droplet formation. The p.N88S mutation leads to an abnormal N- glycosylation site and unfolded protein aggregation leading to endoplasmic reticulum stress and possible secondary motoneuron degeneration.
Note that pathogenic null variants in the same BSCL2 gene are associated with an autosomal recessive congenital generalized lipodystrophy (type 2) and that exon 7 skipping due to the c.985C>T variant results in an early-onset progressive encephalopathy.
BSCL2