Novel mutation in patients with microcephalic osteodysplastic primordial dwarfism type II (MOPD II)

A rare type of autosomal recessive skeletal disorder, known as microcephalic osteodysplastic primordial dwarfism (MOPD) type II, causes a wide range of clinical abnormalities, including skeletal dysplasia, microcephaly, abnormal skin pigmentation, insulin resistance, typical facial features, and severe tooth deformities. Given the diverse manifestations of MOPD disorders and the overlapping clinical characteristics among primordial dwarfism (PD) subtypes, mutation analysis is crucial for accurate diagnosis and confirmation of MOPD II. In this study, whole-exome sequencing (WES) and GAP-PCR were employed to identify relevant genetic variants in three patients suspected of having MOPD. The clinical characteristics of three Iranian patients exhibiting hallmark features of MOPD were assessed. All patients were the offspring of consanguineous marriages and were referred from various provinces of Iran. WES was performed, and the identified variants were prioritized according to the standard filtration criteria. In the next step, Sanger sequencing was conducted to validate the candidate variants identified through WES in patients and their parents. Finally, GAP-PCR was implemented to resolve conflicting results between WES and Sanger sequencing for one of the patients. Analysis of three distinct cases revealed a novel homozygous copy number variation (CNV) in Case 3, consisting of a 490 bp deletion harboring exon 19 in the PCNT gene. Additionally, a nonsense homozygous variant in the PCNT gene (c.2812 C > T, p.Gln 938*) was found in Cases 1 and 2. This pathogenic variant has been previously documented in the literature. Reporting a novel deletion in the PCNT gene improves genetic testing services, including PND and pre-implantation genetic diagnosis (PGD) for MOPD II.