Exploring the clinical and mutational spectrum of MORC2-associated disorders.

MORC2 missense variants; the p.Ser87Leu variant, which defines the neuromuscular cluster, is distinguished by a significant reduction in protein level on western blot, with no overall difference between variants associated with the neuromuscular and DIGFAN forms.

Pathogenic missense variants in MORC2 are associated with two distinct disorders, Charcot-Marie-Tooth disease type 2Z and the recently described DIGFAN phenotype combining developmental delay, impaired growth, dysmorphic facies and axonal neuropathy, whose manifestations vary widely between individuals. The authors collected clinical and imaging data from 16 patients and performed western blot analysis after transfection of HEK293T cells for ten variants identified in patients plus two novel variants without clinical data. Eleven different missense variants were identified in the cohort, four of them novel, and early-onset forms separated into two principal neurological phenotypes, one predominantly neuromuscular and one central nervous system-predominant. The p.Ser87Leu variant, which defines the neuromuscular cluster, was distinguished by a significant reduction in protein level, whereas no statistically significant difference in expression appeared between variants associated with Charcot-Marie-Tooth type 2Z and those associated with DIGFAN.

Synthesis written by Geno'X. For the full original abstract, please refer to the source publication.

The clinically useful point is the separation into two pictures, purely neuromuscular or with predominant central involvement, with one variant, p.Ser87Leu, pointing to the former: that is prognostic information to convey when a MORC2 result comes back. The mechanistic demonstration remains limited, however, since protein level does not discriminate the two entities apart from that variant, which argues against concluding too quickly that loss of expression is the whole story. Sixteen patients for eleven different variants makes for a still fragile genotype-phenotype correlation, which the authors honestly present as a trend to be confirmed.

Analysis by Dr Thibaut Benquey