Molecular Genetics & Genomic Medicine

BACKGROUND: Congenital aniridia is a severe autosomal dominant binocular developmental disorder, the primary feature of which is congenital absence or hypoplasia of the iris. PAX6 is the main disease-causing gene of congenital aniridia; inheritance is autosomal dominant. But the current mutations do not fully explain this disorder. METHODS: We investigated the mutation profile of genes related in three Chinese families with congenital aniridia through targeted sequencing technology...

BACKGROUND: Early-onset Parkinson's disease (PD) is the most common inherited form of parkinsonism, with the PRKN gene being the most frequently identified mutated. Exon rearrangements, identified in about 43.2% of the reported PD patients and with higher frequency in specific ethnicities, are the most prevalent PRKN mutations reported to date in PD patients. METHODS: In this study, three consanguineous families with early-onset PD were subjected to whole-genome sequencing (WGS) analyses that were followed by Sanger sequencing and droplet digital PCR to validate and confirm the disease segregation of the identified genomic variations and to determine their parental origin...

BACKGROUND: Clinical diagnostic whole-exome sequencing (WES) is a powerful tool for patients with undiagnosed genetic disorders. To demonstrate the clinical utility, we surveyed healthcare providers (HCP) about changes in medical management and treatment, diagnostic testing, reproductive planning, and use of educational services subsequent to WES testing. METHODS: For a period of 18 months, an 18-question survey was sent to HCPs attached to the WES reports. We analyzed the molecular diagnosis, patient clinical features, and the medical management changes reported in the returned surveys...

BACKGROUND: General practitioners (GPs) have an increasing role in referring patients with putative mutation in BRCA1/2 genes for genetics consultation and for long-term follow-up of mutation carriers. METHODS: We compared the expectations of the GPs' role according to BRCA1/2 mutation carriers and to GPs themselves. RESULTS: Overall, 38% (58/152) of eligible GPs and 70% (176/252) of eligible patients were surveyed. Although 81% of GPs collected the family history, only 24% considered that they know criteria indicating genetics consultation and 39% sufficient knowledge of BRCA1/2 guidelines to answer patients' questions...

BACKGROUND: Hereditary Non-Polyposis Colorectal cancer is caused by Lynch Syndrome (LS; an autosomal dominant condition) or by Familial Colorectal Cancer Type-X (FCCTX; a condition of high family risk that fulfills Amsterdam criteria). The lifetime risk of developing colorectal cancer (CRC) in FCCTX family members is high and CRC occurs later than in LS. METHODS: To determine the impact of primary prevention colonoscopic screening in asymptomatic first-degree relatives of incident CRC cases in 20 families with FCCTX, we compared cancer incidence and survival in 79 males and 83 females, assumed to be at 50% risk of inheriting a genetic CRC susceptibility factor, who entered screening to an unscreened control group from the families, matched for age at entry into screening and for sex...

BACKGROUND: According to the Catalogue of Transmission Genetics in Arabs, less than half of diseases reported in Lebanese patients are mapped. In the recent years, Next Generation Sequencing (NGS) techniques have significantly improved clinical diagnosis, compared to traditional sequencing methods. METHODS: A total of 213 analyses by NGS (167 by whole exome sequencing (WES) and 46 by multigene panels tests) were performed on pediatric patients across different regions of Lebanon over a period of two years (December 2015-December 2017)...

BACKGROUND: Hemophilia B is an X-linked recessive disorder caused by mutations in the F9 on Xq27.1. Mainly males are affected but about 20% of female carriers have clotting factor IX activity below 0.40 IU/ml and bleeding problems. Fragile-X syndrome (FMR1) and FRAXE syndrome (AFF2) are well-known causes of X-linked recessive intellectual disability. Simultaneous deletion of both FMR1 and AFF2 in males results in severe intellectual disability. In females the phenotype is more variable...

BACKGROUND: Familial adenomatous polyposis (FAP) is a familial colorectal cancer predisposition syndrome characterized by the development of numerous colorectal polyps, which is inherited in an autosomal dominant manner. FAP is caused by germ line mutations in adenomatous polyposis coli (APC) gene. Here, we described the identification of a causative APC gene deletion associated with FAP in an Iranian family. METHODS: Diagnosis of FAP was based on clinical findings, family history, and medical records (colonoscopy and histopathological data) after the patients were referred to Reza Radiotherapy and Oncology Center, Iran, for colonoscopy...

BACKGROUND: Genetic providers face the challenge of having adequate time to conduct a comprehensive evaluation. Hypermobile Ehlers-Danlos (hEDS) syndrome has a complex array of symptoms. An initial visit can involve approximately 60-80 min and an additional 45 min for the check-in and checkout process. We propose a model to improve clinic flow and patient satisfaction by using: (a) pre-appointment questionnaire (b) disease information sheet outlining basic management and (c) itinerary detailing the visit...

BACKGROUND: The purpose of our study was to compare the incidence of chromosomal abnormalities of fetuses with isolated fetal ventriculomegaly (VM) to that of fetuses with the sole risk factor of being born to mothers of advanced age. METHOD: This prospective study included two groups. Group 1 included fetuses with isolated VM and were further categorized according to maternal age, fetal gender, laterality of VM (unilateral or bilateral), evolution of VM (resolved or persistent or progressive), and the gestational age at the time of diagnosis (<28w or ≥28w)...

BACKGROUND: The aim of this study was to use the liquid chromatography/tandem mass spectrometry (LC-MS/MS) method to quantitate levels of three urinary glycosaminoglycans (GAGs; dermatan sulfate [DS], heparan sulfate [HS], and keratan sulfate [KS]) to help make a correct diagnosis of mucopolysaccharidosis (MPS). METHODS: We analyzed the relationships between phenotypes and levels of urinary GAGs of 79 patients with different types of MPS. RESULTS: The patients with mental retardation (n = 21) had significantly higher levels of HS than those without mental retardation (n = 58; 328...

BACKGROUND: Parkinson's disease (PD) is a neurodegenerative disorder which mainly affects the elderly population of various societies. The main hallmark of this disease is the loss of dopaminergic (DA) neurons. So far, numerous studies have implied the role of microRNAs in fine-tuning cellular processes including apoptosis. Studies have also shown that miR-34a is mainly involved in age-related disorders including Alzheimer's disease, and its expression is usually higher in the brain sample patients...

BACKGROUND: A relationship between hypovitaminosis D and infection with HIV and HCV has been established in the scientific literature. Studies comparing these illnesses to other risk factors for development of hypovitaminosis D, such as being of Middle Eastern origin, have been lacking. The goals of this study were: (a) to document vitamin D levels in groups of individuals at high risk of developing its deficiency, (b) analyze the data collected to numerically determine which group had the lowest average vitamin D levels, and (c) discuss the impact of the findings and offer possible explanations...

BACKGROUND: Basal cell carcinoma (BCC) is the most common type of skin cancer. The underlying mechanism leading to BCC formation is not fully uncovered. The aim of this study was to characterize miRNA-451a as a novel tumor suppressor in cutaneous BCC. METHODS: We first evaluated miRNA-451a level in human BCC clinical tissues and inducible BCC mouse model. Then we studied the impact of overexpressing or inhibiting miR-451a in cell proliferation, colony formation potential, and cell cycle pattern...

BACKGROUND: Hereditary myopathy with lactic acidosis (HML) is an autosomal recessive disease caused by an intron mutation in the iron-sulfur cluster assembly (ISCU) gene. The mutation results in aberrant splicing, where part of the intron is retained in the final mRNA transcript, giving rise to a truncated nonfunctional ISCU protein. Using an ISCU mini-gene system, we have previously shown that PTBP1 can act as a repressor of the mis-splicing of ISCU, where overexpression of PTBP1 resulted in a decrease of the incorrect splicing...

BACKGROUND: Genomic medicine is rapidly evolving, particularly in the domain of reproduction. Population carrier screening for a range of disorders is becoming possible using whole genome/exome sequencing. However, very little is known about the views of genetically disabled adults toward selective reproduction. METHODS: Forty-three in-depth qualitative interviews were carried out with adults living with different types of genetic condition, recruited through support groups and clinics...

BACKGROUND: Congenital scoliosis (CS) is defined as a lateral curvature of the spine due to the vertebral malformations and has an incidence of 0.5-1/1,000 births. We previously examined TBX6 in Japanese CS patients and revealed that approximately 10% of CS was caused by TBX6 mutations. However, the genetic cause of remaining CS is unknown. METHODS: We recruited 78 CS patients without TBX6 mutations and major comorbidities, and investigated the genes previously reported to be associated with CS and congenital vertebral malformations by whole-exome sequencing...

BACKGROUND: Beta-galactosidase-1 (GLB1) is a lysosomal hydrolase that is responsible for breaking down specific glycoconjugates, particularly GM1 (monosialotetrahexosylganglioside). Pathogenic variants in GLB1 cause two different lysosomal storage disorders: GM1 gangliosidosis and mucopolysaccharidosis type IVB. In GM1 gangliosidosis, decreased β-galactosidase-1 enzymatic activity leads to the accumulation of GM1 gangliosides, predominantly within the CNS. We present a 22-month-old proband with GM1 gangliosidosis type II (late-infantile form) in whom a novel homozygous in-frame deletion (c...

BACKGROUND: Nasopharyngeal carcinoma (NPC) has a higher incidence in North Africa than in most parts of the world. In addition to environmental factors such as Epstein-Barr virus infection and chemical carcinogen exposure, genetic susceptibility has been reported to play a key role in the development of NPC. NAD(P)H: quinone oxidoreductase 1 is a cytosolic enzyme that protects cells from oxidative damage. A C to T transition at position 609 in the NQO1 gene (OMIM: 125860) has been shown to alter the enzymatic activity of the enzyme and has been associated with increased risk to several cancers...

BACKGROUND: Historically, three founder mutations in the BRCA1/2 (OMIM 113705; OMIM 600185) genes have been the focus of cancer risks within the Ashkenazi Jewish (AJ) population. However, there are several additional mutations associated with increased susceptibility to cancer in individuals of AJ ancestry. METHODS: We report three patients who exemplify the need to keep these additional founder mutations in mind when pursuing hereditary cancer genetic testing of individuals in this population...