Additive dominant effect of a SOX10 mutation underlies a complex phenotype of PCWH

22q11.2q13 duplication including SOX10 causes sex‐reversal and peripheral demyelinating neuropathy, central dysmyelinating leukodystrophy, Waardenburg syndrome, and Hirschsprung disease

“…Perhaps the best known duplication of this region is a recurrent 22q11.2 microduplication (MIM 608363), mediated by low copy repeats (LCRs) and reciprocal to the common 22q11.2 deletion underlying DiGeorge syndrome and velocardiofacial syndrome. Among the dosage‐sensitive genes on 22q is the SOX10 gene (MIM 602229), which belongs to the SOX (SRY‐related HMG‐box) family of genes located on chromosome 22q13.1 (Ito et al, ), centromeric to the common duplication. It is first expressed during embryonic development in cells of the neural crest, and has a critical role in regulation of development of cells in the neural crest lineage.…”

Heterozygous deletion at the SOX10 gene locus in two patients from a Chinese family with Waardenburg syndrome type II

“…The deletion here we reported can however confirm the thesis, considering that such a large deletion surely implies haploinsufficiency and likely doesn't imply other additive effects on this gene. In fact other additive dominant effects of specific mutations are probably at the basis of the more severe peripheral demyelinating disease observed in other waardenburg cases [7]. In this study, we report on a family with two patients with a unique de novo deletion at 22q13.1 region, including SOX10, and presenting with clinical features of WS2.…”

“…Pan et al [11] reported no SOX10 mutations were found in Han Chinese with isolated HSCR, and suggested that the SOX10 gene is unlikely to be a major HSCR gene in the Chinese Han population. Ito et al suggested that the effect of a PCWH-causing SOX10 mutation is solely pathogenic in a dosage-dependent manner in vivo [7]. This additional gene should be a topic for future study.…”

Waardenburg syndrome: a rare cause of inherited neuropathy due to SOX10 mutation

“…Heterozygous SOX10 mutations have been described in patients with WS types 2 and 4. Distinct classes of SOX10 mutations are responsible for a more severe phenotype of this condition evolving peripheral and central nervous system known as PCWH: peripheral demyelinating neuropathy, central dysmyelinating leukodystrophy, Waardenburg syndrome and Hirschprung disease (Inoue et al, ; Ito et al, ) .…”

“…It is selectively expressed in neural crest cells during the early stages of development and can be detected in the sensory, sympathetic, and enteric ganglia and along nerves (Bondurand et al, ; Kuhlbrodt et al, ) . Its expression in the central nervous system occurs later, increasing in strength until adulthood where expression levels are maximal (Kuhlbrodt et al, ; Ito et al, ) . SOX10 regulates the development and maintenance of neural crest derivatives including Schwann cells, melanocytes, and enteric ganglion cells, and also of oligodendrocytes (Kuhlbrodt et al, ; Bondurand and Sham, ) .…”