A novel IGHMBP2 variant and clinical diversity in Vietnamese SMARD1 and CMT2S patients

Abstract

Background: Pathogenic variants in the IGHMBP2 gene are associated with two distinct autosomal recessive neuromuscular disorders: spinal muscular atrophy with respiratory distress type 1 (SMARD1; OMIM #604320) and Charcot-Marie-Tooth type 2S (CMT2S; OMIM #616155). SMARD1 is a severe and fatal condition characterized by infantile-onset respiratory distress, diaphragmatic palsy, and distal muscular weakness, while CMT2S follows a milder clinical course, with slowly progressive distal muscle weakness and sensory loss, without manifestations of respiratory disorder.

Methods: Whole-exome sequencing of the IGHMBP2 gene was performed for eight Vietnamese patients with IGHMBP2-related neuromuscular disorders including five patients with SMARD1 and the others with CMT2S.

Results: We identified one novel IGHMBP2 variant c.1574T > C (p.Leu525Pro) in a SMARD1 patient. Besides that, two patients shared the same pathogenic variants (c.1235 + 3A > G/c.1334A > C) but presented completely different clinical courses: one with SMARD1 who deceased at 8 months of age, the other with CMT2S was alive at 3 years old without any respiratory distress.

Conclusion: This study is the first to report IGHMBP-2-related neuromuscular disorders in Vietnam. A novel IGHMBP2 variant c.1574T > C (p.Leu525Pro) expressing SMARD1 phenotype was detected. The presence of three patients with the same genotype but distinct clinical outcomes suggested the interaction of variants and other factors including relating modified genes in the mechanism of various phenotypes.

Keywords: CMT2S; Charcot–Marie–Tooth type 2S; IGHMBP2; SMARD1; neuromuscular disorders; spinal muscular atrophy with respiratory distress type 1.

Figure 1

Photographs of patient 1 (A–C); patient 4 (D), and patient 5 (E). (A) Patient 1 (4 years old) was fully dependent on mechanical ventilation; (B) fatty pads of the fingers; (C) talipes equinovarus as the consequence of lower limbs muscle weakness. (D) Patient 4 (13 years old) had been wheelchair-bound since the age of 9. (E) Patient 5 (3 years old) had muscle weakness in both arms and legs and required assistance to stand up as shown in the image.

Figure 2

IGHMBP2 analysis and pedigree of the families. Clear, half-shaded, and shaded symbols present unaffected, carrier, and affected individuals, respectively. Variants of family 1 (A), 2 (B), 3 (C), 4 (D), 5 (E), 6 (F), and 7 (G) are inherited from their parents, respectively. The arrows point to the probands.