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.

Keywords: CMT4B; MTMR5; Necklace fibres; SBF1.

Fig. 1

Pedigree of the family with two affected siblings and genetic phenotypes in the family. a Pedigree of the family (black symbols represent affected patients; black arrow points the index patient of the family); b Electropherograms of cDNA for the frameshift deletion in the SBF1 gene (I-1 and I-2 are parents; II-2 is the index patient; control is a normal healthy control); c MTMR5 and actin antibody in fibroblasts (this represents an example of three experiments carried out); d–e Expression level of MTMR5 protein in fibroblasts from the family compared with normal controls (error bar represents the standard deviation; C1–C3 are three normal controls. Hom homozygous, Het heterozygous.)

Fig. 2

Clinical features of the index patient and his sister. a–f and k–m were from the index patient II-2, and h–j were from the affected sister II-1. The tongue of the index patient was atrophic (b); muscle wasting in both calves (c); pes cavus and slim ankle as pointed by arrow in (d); syndactyly of two toes of both feet (e–f) as pointed by arrow, compared to a normal foot (g); abnormal colour of both feet of the affected sister (h–j); syndactyly of two fingers of both hands (k–m) pointed by a small arrow in compared to a normal hand on the right (k), a slim wrist pointed by an arrow in (k), and a surgery scar on left hand pointed by arrow in (m)

Fig. 3

Biopsy features of the index patient. H&E staining showed an increased variation in fibre size and frequent internal nuclei (a); internal nuclei were often distributed in a linear fashion displaced within the fibre and laying along a basophilic line resembling a necklace fibre (arrows in b and c); Gomori trichrome staining showed some increase in the density of mitochondrial staining in a peripheral band in occasional fibres (arrow in d), and there were no ragged red fibres; NADH-TR (e) and SDH (f) staining confirmed the impression of necklace fibres with an increase in the intensity of peripheral staining with a band-like pattern; (g) showed some desmin-positive staining in the peripheral band of many fibres; and (h) showed fine granular p62-positive staining along the ring visible in a necklace fibre. Necklace fibres are indicated by arrows. Scale bar represents 100 μm in a; 50 μm in b and d; 25 μm in c and e–h

Fig. 4

Brain and spinal cord MRI of the siblings. Upper lane: a focus mature damage in the periaqueductal grey matter of the upper tegmentum was observed in the index patient (II-2) (pointed by the red arrow). The cord was mildly thinned throughout. Lower lane: the sibling (II-1) showed mild volume loss of the lateral folia of both cerebellar hemispheres in keeping with mild cerebellar atrophy; there is abnormality in the posterior and middle area of the midbrain (pointed by the red arrow), involving symmetrically the medial longitudinal fasciculus and extending into the red nuclei; the diameter of spinal cord is smaller than expected which indicates some grade of cord atrophy