A Recurrent Pathogenic Variant of INPP5K Underlies Autosomal Recessive Congenital Muscular Dystrophy With Cataracts and Intellectual Disability: Evidence for a Founder Effect in Southern Italy

Abstract

Inositol polyphosphate-5-phosphatase K [INPP5K (MIM: 607875)] acts as a PIP₃ 5-phosphatase and regulates actin cytoskeleton, insulin, and cell migration. Biallelic pathogenic variants in INPP5K have recently been reported in patients affected by a form of muscular dystrophy with childhood onset. Affected patients have limb girdle muscle weakness, often associated with bilateral cataracts, short stature, and intellectual disability. Here we report four patients affected by INPP5K-related muscle dystrophy, who were apparently unrelated but originated from the same geographical area in South Italy. These patients manifest a recognizable phenotype characterized by early onset muscular dystrophy associated with short stature and intellectual disability. All affected subjects were homozygous or compound heterozygous for the c.67G > A (p.Val23Met) missense change and shared a common haplotype, indicating the occurrence of a founder effect.

Keywords: CMD; INPP5K; LGMD; cataract; short stature.

FIGURE 1

Transverse T1-weighted MRI of thighs and calf muscles of patients harboring INPP5K mutations. Pt #1 (A,D), Pt #2 (B,E), Pt #3 (C,F), pt #4 (D,G). At thigh level, an involvement of vasti muscles (V) are relative sparing of rectus femoris (RF) in patients #1and #4 (A,D). In the posterior thigh, sartorius (Sar), gracilis (Gra), and to a lesser extent, semitendinosus (ST) were relatively spared (E,H). At the lower leg level, anterolateral compartment (tibialis anterior-T ant- and peronei –Per-) and soleus (Sol) were similarly affected, with relative sparing of both gastrocnemii (GMed and GLat) muscles mainly in #4 (H). In the youngest patient, the MRI did not disclose significant abnormalities (C,G) on T1-weighted images.

FIGURE 2

The common haplotype showing the minimal common region among the six patients. As can be seen, the nine alleles with the INPP5K c.67G > A variant (in red) shared a common region between rs3752827 and rs7342891 (213 kb). In blue, the other three INPP5K variants in compound heterozygosis with the founder c.67G > A variant. Segregation analysis in both parents of the six patients allowed to reconstruct parental genotype. P, paternal allele; M, maternal allele. * Patient already reported by Osborn et al. (2017).