Association of a Novel Nonsense Mutation in KIAA1279 with Goldberg-Shprintzen Syndrome.

Goldberg-Shprintzen syndrome (OMIM 609460) (GOSHS) is an autosomal recessive multiple congenital anomaly syndrome distinguished by intellectual disability, microcephaly, and dysmorphic facial characteristics. Most affected individuals also have Hirschsprung disease and/or gyral abnormalities of the brain. This syndrome has been associated with KIAA1279 gene mutations at 10q22.1. Here we report a 16 yr old male patient referred to Center for Comprehensive Genetic Services, Tehran, Iran in 2015 with cardinal features of GOSHS in addition to refractory seizures. Whole exome sequencing in the patient revealed a novel nonsense (stop gain) homozygous mutation in KIAA1279 gene (KIAA1279: NM_015634:exon6:c.C976T:p.Q326X). Considering the wide range of phenotypic variations in GOSHS, relying on phenotypic characteristics for discrimination of GOSH from similar syndromes may lead to misdiagnosis. Consequently, molecular diagnostic tools would help in accurate diagnosis of such overlapping phenotypes.

First Case Report of EX3del4765 Mutation in PAH Gene in Asian Population.

INTRODUCTION: Phenylketonuria (PKU) is an autosomal recessive inborn error of phenylalanine metabolism, which is caused by mutation in phenylalanine hydroxylase (PAH) gene. Most of the PAH mutations are missense mutations (67%), which are followed by small or large deletions (13%). CASE PRESENTATION: We reported a patient with classic PKU and his parents harboring a large deletion in exon 3 (EX3del4765) of PAH gene. This is the first case report of EX3del4765 in Asian patients with PKU. CONCLUSIONS: This finding may help improve early detection, differential diagnosis, genetic counseling, and even treatment of patients with PKU.

Mutation Spectra of BRCA Genes in Iranian Women with Early Onset Breast Cancer - 15 Years Experience.

Breast cancer is the most common cancer in Iran. In the recent years an upward trend has been observed in the Iranian population. Early detection by molecular approaches may reduce breast cancer morbidity and mortality. We provided consultation to 3,782 women diagnosed with early onset breast cancer during the past 15 years (1999-2014). To establish a data set for BRCA gene alterations of the Iranian families at risk, two hundred and fifty four women who met our criteria were analyzed. A total number of 46 alterations including 18 variants with unknown clinical significance (39.1%), 18 missense mutations (39.1%), 7 Indels (15.2%) and 3 large rearrangement sequences (6%) were identified. Further scanning of affected families revealed that 49% of healthy relatives harbor identical causative mutations. This is the first report of comprehensive BRCA analysis in Iranian women with early onset breast cancer. Our findings provide valuable molecular data to support physicians as well as patients for the best decision making on disease management.

A new approach for molecular diagnosis of TAR syndrome.

Thrombocytopenia-absent radius (TAR) syndrome is a rare genetic disorder inherited in an autosomal recessive fashion. In most patients chromosomes at 1q21.1 harbor a 200-kb deletion consisted of many genes, including RBM8A. We aimed to examine a cost-effective method for investigation a consanguineous family clinically diagnosed as TAR syndrome. A comprehensive sequencing of RBM8A identified several SNPs including two low-frequency regulatory SNPs (rs139428292 and rs201779890) in the father, the mother and the proband in which they carried A/G, G/- and A/- alleles for rs139428292, respectively. They also had G/G genotype in the father, G/- in both mother and proband for rs201779890. In addition a SNP (rs872786) was found in mother as T/- allele while father and proband have possessed A/A and A/- alleles, respectively. Further investigation determined a rare null allele in the proband using quantitative real-time PCR. We concluded that compound inheritance of a rare null allele and one of the two low-frequency noncoding SNPs (rs139428292) in RBM8A are crucial for TAR syndrome. Quantitative real-time PCR and Sanger sequencing may recruit for molecular diagnosis of TAR rather than molecular cytogenetic study.

Mutation spectra of the AAAS gene in Iranian families with Allgrove Syndrome.

BACKGROUND AND AIMS: Allgrove (OMIM#231550) or Triple-A syndrome is a rare, autosomal recessive disorder characterized by the triad of familial adrenal insufficiency, achalasia, and alacrima. Approximately one-half of all patients with Triple-A syndrome have been shown to have mutations in the AAAS gene on chromosome 12q13, which results in loss or non-function of the encoded protein. METHODS: Five unrelated families clinically diagnosed with Allgrove Syndrome were evaluated for sequence variations in the AAAS gene. Blood samples were collected after informed and written consent was obtained. Isolated DNA derived from subjects was amplified using intronic primers. The entire sequence of the AAAS gene including regulatory region, coding regions and exon-intron boundaries were analyzed for any alteration by PCR and direct sequencing. RESULTS: In six probands of five families, four previously reported and two novel mutations were identified. Two heterozygote and homozygote mutations in exon 9 and the regulatory region, respectively, were detected in one of the probands. CONCLUSIONS: This is the first report of Triple-A syndrome from an Iranian population. Collectively, our study findings indicate that mutations scattered across the AAAS gene and upstream regulation elements. Various ethnic groups should develop a mutation database for their own rare genetic disorders. However, mutation databases should initially screen common mutated alleles. Our families present the typical triad of symptoms and the mutation spectrum is similar to the other population studied. Further study is required for phenotype-genotype correlation in the Iranian population.