Compound Heterozygous Mutation of IGHMBP2 Presenting with Variable Phenotypes in 4 siblings


Clinical Management

Poster Number: T395


Leigh Maria Ramos-Platt, MD, Children's Hospital Los Angeles, Ryan Chowdhury, medical student year 2, Keck School of Medicine, Matthew Deardorff, MD, PhD, Children's Hospital Los Angeles, Taylor Shannon, MD, Children's Hospital Los Angeles

Background: Recessive abnormalities in IGHMBP2 have been associated with both Spinal Muscular Atrophy Respiratory Distress (SMA-RD) and Charcot Marie Tooth (CMT) phenotypes.

Objectives. To report on a family of 4 affected siblings from a non-consanguineous family that had both phenotypes (2 of each phenotype) with unaffected parents.

Results: All siblings carried the IGHMBP2(NM_002180.3):c.660A>C (p.Lys220Asn) change. This was inherited from their father. The 2 siblings with the CMT phenotype had as a second change: c.2911_2912del (p.Arg971GlufsTer4). The 2 siblings that had as a second change: c.92G>A (p.Trp31Ter). This was inherited from their mother.

IGHMBP2(NM_002180.3):c.2911_2912del (p.Arg971GlufsTer4) is predicted to be pathogenic. IGHMBP2(NM_002180.3):c.92G>A (p.Trp31Ter) is a nonsense mutation and is pathogenic. IGHMBP2(NM_002180.3):c.660A>C (p.Lys220Asn) is likely pathogenic.

The 2 SMA-RD siblings presented in their first few months of life and required tracheostomy, ventilator, and G-tube support. They shared the history of being IUGR and had liver enzyme elevations. One of the siblings was symptomatic at birth. The other developed progressive weakness in her cry at 1 month of age associated with COVID infection. The 2 CMT siblings attained their early motor developmental milestones on time (one walking by 12 months’ and the other at 13-14 months’ of age). Both were noted to be persistent toe walkers and had weakness of dorsiflexion greater than plantarflexion. One required serial casting and the other articulated braces. All siblings are of normal intelligence.

This family series concludes (1) clinical presentations may be predicted based on varied mutations in the same gene (2) even in families, it is important to get each member tested and not assume that they all have the same mutation (3) mutations in the IGHMBP2 may have an effect on more than just the nervous system.