CD151, a member of the tetraspanin family, is essential for normal development of skin and kidney. To date, only 2 pathogenic variants of the <i>CD151</i> gene have been identified in a related disorder with recessive inheritance. Here, in the third study of <i>CD151</i> mutations, we report 3 affected siblings presenting variable degrees of renal and dermal symptoms. Whole exome sequencing (WES) was performed on the proband, followed by data analysis and in silico assessments. Confirmation of the mutation in the other patients were carried out using Sanger sequencing. The consequence of the <i>CD151</i> mutation was investigated by RNA extraction and Sanger sequencing of PCR products from cDNA. Multiple computational tools were applied for protein alignment, homology modeling, and molecular interaction analysis. WES revealed the variant c.351+2T&#x3e;C, NM_139029 (GRCh37) in <i>CD151</i>, and this was confirmed by Sanger sequencing in all patients. This variant is the result of a substitution of nucleotide T with C that changes the position +2 of the donor splice site in intron 5, leading to total loss of exon 5 from the transcript. The mentioned variant was not found in population allele frequency databases, and prediction tools concurred in its damaging effect on the protein. Based on the criteria from ACMG guidelines, this variant is pathogenic. Interestingly, in terms of clinical findings, symptoms and severity of the disease in the patients in this study were different compared to the previous report of the mutation and the disease. In addition, in silico analysis in this study appears to suggest a candidate protein, Tetraspanin-11 (TSPAN11), that could partially modify CD151 functions. This study supports the pathogenic effect of the <i>CD151</i> variant c.351+2T&#x3e;C, highlights the extensive variable expressivity amongst patients, reinforces the contribution of genomic content to clinical characteristics of <i>CD151</i> mutations, and accentuates the importance of modifier genes.

Objectives:The purpose of this study was to investigate CYP21A2 mutations in Iranian congenital adrenal hyperplasia (CAH) patients. Methods: In 25 patients, the first PCR was done to distinguish the gene from the pseudogene (identification of chimeras). Then, second PCR was performed in the patients who had not chimeras, followed by complete exons and introns of CYP21A2 sequencing to distinguish the mutations. Results: Complex alleles comprising three compound heterozygote mutations were identified; p.I173N/exon 6 cluster (15.7%), p.I173N/exon 6 cluster/p.V282L (47.3%) and IVS2-13A>C, G/exon 6 cluster/p.V282L (5.2%). In order to confirm the accuracy of mutations, the parents of the patients were also analyzed. In each family, one of the parents had a heterozygote variant (p.I173N/p.V282L) and the other had exon 6 cluster heterozygote variant without any symptoms of the disease. Two different mutations in the heterozygous state, exon 6 cluster (10.5%) and exon 6 cluster/p.V282L (5.2%) and p.G110Efs the 8 nucleotide deletion in exon 3 (5.2%), I173N in the heterozygote state (10.5%). A high frequency of variants was found in CYP21A2, including: rs6477 (56%), rs6468 (8%), rs6474 (12%), rs6472 (16%), rs6473 (16%), rs6446 (16%), rs61338903 (32%) and rs193922546, rs530758070, rs11970671, rs61732108, rs778403992, rs1058152 and rs562025438 (each 4%). Conclusions: The present study showed that the compound heterozygosity and complex alleles are the most frequent cause of congenital adrenal hyperplasia in Iranian population. Patients' clinical manifestations were correlated with mutated alleles and the residual activity of 21-hydroxylase enzyme. Based on diversity of mutations in CAH patients of this study, whole CYP21A2 gene sequencing would be preferential approach in analyzing CAH patients in our population.