An infant with congenital respiratory insufficiency and diaphragmatic paralysis: A novel BICD2 phenotype?

Abstract

Monoallelic pathogenic variants in BICD2 are associated with autosomal dominant Spinal Muscular Atrophy Lower Extremity Predominant 2A and 2B (SMALED2A, SMALED2B). As part of the cellular vesicular transport, complex BICD2 facilitates the flow of constitutive secretory cargoes from the trans-Golgi network, and its dysfunction results in motor neuron loss. The reported phenotypes among patients with SMALED2A and SMALED2B range from a congenital onset disorder of respiratory insufficiency, arthrogryposis, and proximal or distal limb weakness to an adult-onset disorder of limb weakness and contractures. We report an infant with congenital respiratory insufficiency requiring mechanical ventilation, congenital diaphragmatic paralysis, decreased lung volume, and single finger camptodactyly. The infant displayed appropriate antigravity limb movements but had radiological, electrophysiological, and histopathological evidence of myopathy. Exome sequencing and longread whole-genome sequencing detected a novel de novo BICD2 variant (NM_001003800.1:c.[1543G>A]; [=]). This is predicted to encode p.(Glu515Lys); p.Glu515 is located in the coiled-coil 2 mutation hotspot. We hypothesize that this novel phenotype of diaphragmatic paralysis without clear appendicular muscle weakness and contractures of large joints is a presentation of BICD2-related disease.

Vocal cord paralysis in autosomal dominant spinal muscular atrophy due to BICD2

“…To date, SMALED2B patients have been reported to present with respiratory insufficiency and survive only to early childhood 3 . Although congenital diaphragmatic paralysis was reported in a patient who was confirmed to be a BICD2 variant, 4 previous reports did not describe vocal cord paralysis in SMALED2 patients. We speculate that congenital vocal cord paralysis may occur in SMALED2B patients with respiratory insufficiency, and be a presentation in other BICD2 ‐related diseases.…”

Mitofusin 2 Variant Presenting With a Phenotype of Multiple System Atrophy of Cerebellar Subtype

“…Long-read genome sequencing was performed as previously described on the Oxford Nanopore Technologies PromethION. 8 …”