NPHP3 splice acceptor site variant is associated with infantile nephronophthisis and asphyxiating thoracic dystrophy; A rare combination.

Nephronophthisis (NPHP) is a group of rare inherited ciliopathy disorders characterized by the multicystic dysplastic kidney, oligohydramnios, and tubulointerstitial nephritis that progresses to end-stage renal disease (ESRD). NPHP is a clinically and genetically heterogeneous disorder with extrarenal symptoms including skeletal deformities, nervous system anomalies, and ophthalmologic features. Three clinical subtypes, infantile, juvenile, and adolescent, have been recognized based on age of onset of ESRD. Infantile nephronophthisis with asphyxiating thoracic dystrophy is a very rare association. Here, we investigated a consanguineous family having two neonates with a clinical phenotype of lethal infantile NPHP associated with asphyxiating thoracic dystrophy. Whole exome sequence data analysis identified a splice acceptor site variant (Chr3-132408107-CCT-C; NM_153240.4: c.2694-2_2694-1del) in the NPHP3 gene. The segregation of a variant in the family was confirmed by Sanger sequencing. The lethal phenotype in our case might be due to respiratory insufficiency secondary to a severely restricted thoracic cage. Present work is an exclusive depiction of lethal infantile NPHP phenotype in association with asphyxiating thoracic dystrophy that has not been reported before in families segregating NPHP3 mutations. Moreover, this work expands the phenotypic spectrum of NPHP3 variants. Overall, our findings add to the increasing body of evidence that mutations in ciliary genes/proteins show pleiotropic effects with phenotypic overlap between related disorders and apparently unrelated clinical entities.

A Novel Frameshift Mutation in the ITGB3 Gene Leading to Glanzmann's Thrombasthenia in a Saudi Arabian Family.

Glanzmann's thrombasthenia (GT) is an autosomal recessive congenital bleeding disorder of platelet aggregation. Mutations in ITGA2B and ITGB3 genes result in quantitative and/or qualitative abnormalities of the glycoprotein receptor complex IIb/IIIa (integrin αIIbß3), which in turn impairs platelet aggregation and lead to GT. In this study, whole genome single nucleotide polymorphism (SNP) genotyping as well as whole exome sequencing was performed in a large family segregating GT. Analysis of the genotypes localized the disease region to chromosome 17q21.2-q21.3. Filtration of whole exome data and candidate variants prioritization identified a pathogenic variant in the ITGB3 gene. The single nucleotide deletion variant (c.2113delC) in exon 13 of the ITGB3 gene is predicted to cause a frameshift and absence of vital C-terminal domains including the transmembrane helix and the cytoplasmic domain. Clinical variability of the bleeding phenotype in affected individuals with the same mutation suggests that other genetic and nongenetic factors are responsible for determining GT features.

A Heterozygous Mutation in the Triple Helical Region of the Alpha 1 (II) Chain of the COL2A1 Protein Causes Non-Lethal Spondyloepiphyseal Dysplasia Congenita.

Objective:Heterozygous pathogenic variants in the COL2A1 gene result in several clinical features including impaired skeletal growth, ocular and otolaryngological abnormalities. Missense mutations in the triple helical region of the COL2A1 protein have been associated with lethal spondyloepiphyseal dysplasia (SED). In this study, we aimed to identify the underlying cause of a case of SED congenita (SEDC) in a 27-month-old child. Materials and Methods: A patient who was diagnosed initially with osteochondrodysplasia underwent a detailed clinical and radiological examination to obtain a conclusive diagnosis. The patient did not show any clinical features of hypochondrogenesis. Whole exome sequencing of the COL2A1 gene was carried out to identify the underlying genetic cause of the disorder. Results: Variant annotation and filtration detected a heterozygous missense mutation c.1357G>A (p.G453S) in the exon 21 of the COL2A1 gene of the proband which was confirmed by Sanger sequencing. Neither parent carried the mvariant suggesting this was a new mutation. Conclusion: The COL2A1 mutation (c.1357G>A), identified in this case, results in more mild phenotype than other missense mutations in exon 21 which are known to cause lethal hypochondrogenesis. We showed, for the first time, that a missense mutation (p.G453S) in the triple helical region of the alpha 1 (II) chain of the COL2A1 protein underlies SEDC and is not always lethal.