Microcephalic osteodysplastic primordial dwarfism type II: Additional nine patients with implications on phenotype and genotype correlation

Abstract

PCNT encodes a large coiled-protein localizing to pericentriolar material and is associated with microcephalic osteodysplastic primordial dwarfism type II syndrome (MOPD II). We report our experience of nine new patients from seven unrelated consanguineous Egyptian families with the distinctive clinical features of MOPD II in whom a customized NGS panel showed homozygous truncating variants of PCNT. The NGS panel results were validated thereafter using Sanger sequencing revealing three previously reported and three novel PCNT pathogenic variants. The core phenotype appeared homogeneous to what had been reported before although patients differed in the severity showing inter and intra familial variability. The orodental pattern showed atrophic alveolar ridge (five patients), rootless tooth (four patients), tooth agenesis (three patients), and malformed tooth (three patients).In addition, mesiodens was a novel finding found in one patient. The novel c.9394-1G>T variant was found in two sibs who had tooth agenesis. CNS anomalies with possible vascular sequelae were documented in two male patients (22.2%). Simplified gyral pattern with poor development of the frontal horns of lateral ventricles was seen in four patients and mild thinning of the corpus callosum in two patients. Unilateral coronal craniosynstosis was noted in one patient and thick but short corpus callosum was an unusual finding noted in another. The later has not been reported before. Our results refine the clinical, neuroradiological, and orodental features and expand the molecular spectrum of MOPD II. K E Y W O R D S microcephalic osteodysplastic primordial dwarfism, MOPD II, orodental anomalies, PCNT, rootless teeth, tooth agenesis

A Novel PCNT Frame Shift Variant (c.7511delA) Causing Osteodysplastic Primordial Dwarfism of Majewski Type 2 (MOPD II)

“…Also, homozygous and mixed heterozygous PCNT variants were identified in 4 cases from 2 unrelated Thai families suffering from MOPD II ( 28 ). The variant identified in our study is compatible with the variant identified by Piane et al in an Italian patient, and one case that was reported by Abdel-Salam et al ( 14 , 29 ), which was frame-shift variant and resulted in the creation of a premature stop codon and a truncated protein. Up to now, based on Human Gene Mutation Database (HGMD) ( www.hgmd.cf.ac.uk/ ), 53 different pathogenic variants causing MOPD II have been reported.…”

“…Generalized brachydactyly was also noted in the present case similar to the case reported by Weiss et al (35). Clinodactyly, as another skeletal abnormality, is also prevalent among the patients with MOPD II, which was absent in the current case (29,30). Dental abnormalities like Oligodontia, are also hallmark features of MOPD II, which were identified in the present case.…”

“…Microcephaly and skeletal dysplasia are recognized as major hallmarks of MOPD II that have been reported in many cases with MOPD II including the present case (29,30,35,36). Generalized brachydactyly was also noted in the present case similar to the case reported by Weiss et al (35).…”

Clinical relevance of targeted exome sequencing in patients with rare syndromic short stature

“…The pericentrin gene ( PCNT ) [OMIM #605925] encodes a large coiled-coil protein that localizes to the pericentriolar material, where it interacts with several structural centrosomal proteins, including γ-tubulin and PCM1, involved in centrosome function and spindle assembly [ 33 ]. The perturbation of cell division not only affects brain size but also body size [ 34 ]. Of interest, most pathogenic mutations previously reported in patients with MOPD type II are truncation mutations [ 34 , 35 ], whereas our patient had two missense mutations, c.3716G>A (R1239H) and c.7459C>G (L2487V), in PCNT .…”

“…The perturbation of cell division not only affects brain size but also body size [ 34 ]. Of interest, most pathogenic mutations previously reported in patients with MOPD type II are truncation mutations [ 34 , 35 ], whereas our patient had two missense mutations, c.3716G>A (R1239H) and c.7459C>G (L2487V), in PCNT . The R1239H variant was located on the structural maintenance of chromosomes (SMC) protein domain, while L2487V is expected to interact with NEK2, which plays a key role in the regulation of mitotic processes.…”