A novel frameshift deletion in autosomal recessive SBF1-related syndromic neuropathy with necklace fibres

Abstract

Objective To identify the genetic cause of complex neuropathy in two siblings from a consanguineous family. Methods The patients were recruited from our clinic. Muscle biopsy and whole-exome sequencing (WES) were performed. Fibroblasts cell lines from the index patient, unaffected parents, and three normal controls were used for cDNA analysis and western blot. Results The index patient was a 29-year-old male with clinical phenotype of syndactyly, pes cavus, swallowing difficulties, vision problem, imbalance, and muscle weakness. The sibling had similar, but milder symptoms. Nerve conduction studies and electromyography of both patients suggested sensory-motor axonal neuropathy. Muscle biopsy showed a feature of necklace fibres. WES identified a novel homozygous frameshift deletion (c.5477-5478del; p.1826-1826del) in exon 40 of the SBF1 gene in the two siblings, while both parents and the unaffected sibling were heterozygous carriers. Functional analysis showed a markedly reduced level of MTMR5 protein encoded by SBF1 in the index case. The levels of MTMR5 protein in unaffected parents were similar to those found in controls. Conclusion A novel homozygous frameshift deletion in SBF1 was identified in this family. Sensory-motor axonal neuropathy and necklace fibres in biopsy were the major features expanding the phenotypic spectrum of SBF1-related recessive syndromic neuropathy.

Characterization of a novel zebrafish model ofMTMR5-associated CMT4B3

“…Of note, the presence of N-terminal DENN domains is a unique feature of MTMR5 and MTMR13 in the myotubularin family (Laporte et al, 2003). Whilst missense CMT4B3 patient variants (Mégarbané et al, 2010, Nakhro et al, 2013, Alazami et al, 2014, Manole et al, 2016, Romani et al, 2016, Flusser et al, 2018, Gang et al, 2020, Berti et al, 2021) are clustered in the DENN domains and the SBF2 domain (Fig. 1A), suggesting their importance in normal function of MTMR5, pathogenic variants are reported throughout the gene (Landrum et al, 2020), and are associated with loss of expression and/or function (see Supplementary Table 1 for detailed information on the pathogenic variants).…”

“…CMT4B3 is unique as compared to CMT4B1/2 because patients experience signs and symptoms unrelated to peripheral demyelination. These unique clinical features include axonal peripheral neuropathy (Gang et al, 2020), structural brain changes (fork and bracket syndrome) (Romani et al, 2016), intellectual disability (Berti et al, 2021), and alterations in skeletal muscle. The expanded phenotype of CMT4B3 suggests that MTMR5 has functions beyond those specifically related to MTMR2, and also that therapies targeted at CMT4B1/2 may not fully address critical aspects of the CMT4B3 clinical syndrome.…”