The MRN complex consisting of MRE11A- RAD50-NBS1 proteins is involved in the repair of double- strand breaks, and mutations in genes coding for the MRN complex have been identified in families with breast and ovarian cancer. In a BRCA-nega- tive family with positive history of breast and endome- trial cancer, next-generation sequencing-based panel testing identified a mutation in the MRE11A gene (NM_005590 c.1090C>T: p.Arg364Ter). This mutation re- sults in a shorter mutated protein lacking 2 DNA binding domains (the GAR domain and the RAD50 binding site), abolishing the function of protein. This case provides insight into the role of the MRE11A gene in causing breast cancer susceptibility in families, and supports the use of multigene panel testing in cases with hereditary predisposition to breast cancer.
Long QT syndrome type 1 (LQT1) is the most common type of all Long QT syndromes (LQTS) and occurs due to mutations in KCNQ1. Biallelic mutations with deafness is called Jervell and Lange-Nielsen syndrome (JLNS) and without deafness is autosomal recessive Romano-Ward syndrome (AR RWS). In this prospective study, we report biallelic mutations in KCNQ1 in Indian patients with LQT1 syndrome. Forty patients with a clinical diagnosis of LQT1 syndrome were referred for molecular testing. Of these, 18 were excluded from the analysis as they did not fulfill the inclusion criteria of broad T wave ECG pattern of the study. Direct sequencing of KCNQ1 was performed in 22 unrelated probands, parents and at-risk family members. Mutations were identified in 17 patients, of which seven had heterozygous mutations and were excluded in this analysis. Biallelic mutations were identified in 10 patients. Five of 10 patients did not have deafness and were categorized as AR RWS, the rest being JLNS. Eight mutations identified in this study have not been reported in the literature and predicted to be pathogenic by in silico analysis. We hypothesize that the homozygous biallelic mutations identified in 67% of families was due to endogamous marriages in the absence of consanguinity. This study presents biallelic gene mutations in KCNQ1 in Asian Indian patients with AR JLNS and RWS. It adds to the scant worldwide literature of mutation studies in AR RWS. © 2016 Wiley Periodicals, Inc.
Hereditary fructose intolerance (HFI) is a difficult-to-confirm diagnosis, requiring either invasive liver biopsy-enzyme assay or potentially hazardous fructose challenge test or expensive molecular genetic analysis. Therefore, worldwide there has been a trend towards finding "common mutations" in distinct ethnic groups to simplify the process of diagnosis. The nonspecific presentation of the disease often leads to diagnostic confusion with other metabolic liver disorders such as glycogenoses, galactosemia, and tyrosinemia. This leads to much delay in diagnosis with consequent harm to the patient.We report mutations in the ALDOB gene, from eleven Indian patients, seven of whom belong to the Agarwal community. Six patients from the Agarwal community and two non-Agarwal patients harbored one novel mutation, c.324+1G>A (five homozygous and one heterozygous), in the ALDOB gene. Haplotyping performed in families confirmed a founder effect. The community has been known to harbor founder mutations in other genes such as the MLC1, PANK2, and CAPN3 genes, thus providing another evidence for a founder effect in the community in case of HFI. This may pave the path for a simpler and quicker test at least for this community in India. In addition to the founder mutation, we report four other novel mutations, c.112+1delG, c.380-1G>A, c.677G>A, and c.689delA, and a previously reported mutation, c.1013C>T, in the cohort from India.
Multiple suphphatase deficiency (MSD) is an autosomal recessive disorder affecting the post translational activation of all enzymes of the sulphatase family. To date, approximately 30 different mutations have been identified in the causative gene, sulfatase modifying factor 1 (SUMF1). We describe here the mutation analysis of a case of MSD. The proband was a four year old boy with developmental delay followed by neuroregression. He had coarse facies, appendicular hypertonia, truncal ataxia and ichthyosis limited to both lower limbs. Radiographs showed dysostosis multiplex. Clinical suspicion of MSD was confirmed by enzyme analysis of four enzymes of the sulphatase group.
The patient was compound heterozygote for a c.451A>G (p.K151E) substitution in exon 3 and a single base insertion mutation (c.690_691 InsT) in exon 5 in the SUMF1 gene. The bioinformatic analysis of the missense mutation revealed no apparent effect on the overall structure. However, the mutated 151-amino acid residue was found to be adjacent to the substrate binding and the active site residues, thereby affecting the substrate binding and/or catalytic activity, resulting in almost complete loss of enzyme function. The two mutations identified in the present case were novel. This is perhaps the first report of an insertion mutation in SUMF1 causing premature truncation of the protein.
Carpenter syndrome is a rare autosomal recessive disorder characterized by craniosynostosis, polydactyly and syndactyly. The gene Rab23 was identified in 2007, following which there have been only four reports describing different types of mutations. The authors describe herein a case that was diagnosed solely on the basis of history, antenatal ultrasound findings and fetal photographs taken by a cellular phone. Subsequent molecular studies revealed a novel homozygous mutation in the Rab23 gene. This mutation which converted the stop codon into a coding one, results in the formation of a lengthened 307 amino acids protein in contrast to the wild type protein containing 237 amino acids. The secondary structure prediction by PSIpred revealed that the C-terminal region of the longer mutated Rab23 protein contains several helices/strands resulting in the loss of structural flexibility and consequently, prenylation. This made it possible to offer prenatal testing to this family in its next conception where the fetus was unaffected. This case reports a novel molecular mechanism and the utility of integrating the cellular phone into clinical practice.