DMD – Non-syndromic X-linked intellectual disability

Linkage analysis in five families with non-specific X-linked mental retardation (MRX1, MRX10, MRX11, MRX12, MRX13) mapped to regions crossing the brain promoter of DMD, implicating it as a candidate for non-syndromic X-linked intellectual disability through X-linked recessive inheritance (5 families). In one pedigree (MRX12), affected males exhibited hypotelorism and short stature, and heterozygous females showed mild manifestations, but no pathogenic DMD sequence variants were identified in these families ([PMID:1605217]).

Functional studies of the dystrophin Dp186 isoform in Drosophila reveal that loss of Dp186 enhances evoked presynaptic neurotransmitter release and disrupts retrograde signaling, consistent with a synaptic mechanism contributing to cognitive impairment ([PMID:18463264]).

Taken together, the genetic evidence for DMD in non-syndromic X-linked intellectual disability is limited to positional mapping without reported causal variants, while model organism data provide moderate experimental support for a role of brain-specific isoforms in synaptic function. Additional studies sequencing DMD brain‐isoform transcripts in affected males are needed to establish definitive causality.

Key take-home: DMD exhibits limited genetic linkage but moderate functional support for involvement in X-linked intellectual disability, highlighting the need for targeted variant screening of brain-specific dystrophin isoforms.

References

• American journal of medical genetics • 1992 • Localization of non-specific X-linked mental retardation genes. PMID:1605217
• The Journal of Neuroscience • 2008 • The dystrophin Dp186 isoform regulates neurotransmitter release at a central synapse in Drosophila. PMID:18463264

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