dHMN-6

Genetic Context

HGNC-Approved Gene Symbol

IGHMBP2

Gene Full Name

immunoglobulin mu DNA binding protein 2

Chromosome

11q13.3

Zygosity of Responsible Variant

Homozygous or Compound Heterozygous

Variant Mechanism

Loss of Function (LoF)

Details

Mechanistic basis:
Hypomorphic

Confidence:
High

Prediction:
The literature predicts a biallelic loss-of-function mechanism for dHMN-6 (SMARD1): pathogenic IGHMBP2 variants lower the ATPase and helicase activity of the enzyme, and the residual activity a genotype retains tracks severity, running from infantile diaphragmatic paralysis and respiratory failure to a milder later-onset motor phenotype. The nmd mouse, carrying a hypomorphic Ighmbp2 allele, reproduces motor neuron degeneration, and restored wild-type IGHMBP2 is predicted to rescue.

Rationale:
Enzymatic output, not protein identity, sets the phenotype: genotypes retaining measurable helicase activity give later-onset weakness while near-null combinations cause infantile respiratory failure. A graded dose response of that kind follows from a quantitative deficit, and single-variant carriers are unaffected.

ClinVar Pathogenic Variants

View IGHMBP2 ClinVar Variants

ClinGen Curation

View IGHMBP2 ClinGen Curation

dHMN-6 OMIM Entry

dHMN-6 OMIM

IGHMBP2 OMIM Entry

IGHMBP2 OMIM