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Bu J.,Peking University | He S.,University of Chinese Academy of Sciences | Wang L.,Peking University | Li J.,BGI Shenzhen | And 4 more authors.
Indian Journal of Ophthalmology | Year: 2016

Background: Congenital cataract is a rare disorder characterized by crystallin denaturation, which becomes a major cause of childhood blindness. Although more than fifty pathogenic genes for congenital cataract have been reported, the genetic causes of many cataract patients remain unknown. In this study, the aim is to identify the genetic cause of a five-generation Chinese autosomal dominant congenital cataract family. Methods: Whole exome sequencing (WES) was performed on three affected and one unaffected member of the family, known causative genes were scanned first. Sanger sequencing was used to validate co-segregation of the candidate variant in the family. The impact on the transcript and amino acid sequences of the variant was further analyzed. Results: We identified a novel splice donor site mutation c. 2825+1G >A in EPHA2 that was absent in public and in-house databases and showed co-segregation in the family. This variant resulted in an altered splice that led to protein truncation. Conclusions: The mutation we identified was responsible for congenital cataract in our studied family. Our findings broaden the spectrum of causative mutations in EPHA2 gene for congenital cataract and suggest that WES is an efficient strategy to scan variants in known causative genes for genetically heterogeneous diseases. © 2016 Indian Journal of Ophthalmology.

Pen A.E.,Aarhus University Hospital | Nyegaard M.,University of Aarhus | Fang M.,BGI Shenzhen | Jiang H.,BGI Shenzhen | And 17 more authors.
European Journal of Medical Genetics | Year: 2015

We describe a Danish family with an, until recently, unknown X-linked disease with muscular dystrophy (MD), facial dysmorphology and pulmonary artery hypoplasia. One patient died suddenly before age 20 and another was resuscitated from cardiac arrest at the age of 28. Linkage analysis pointed to a region of 25Mb from 123.6Mb to 148.4Mb on chromosome X containing over 100 genes. Exome sequencing identified a single nucleotide splice site mutation c.502-2A>T, which is located 5' to exon 6 in the gene encoding four and a half LIM domain 1 (FHL1) protein. FHL1 expresses three main splice variants, known as FHL1A, FHL1B and FHL1C. In healthy individuals, FHL1A is the predominant splice variant and is mainly found in skeletal and cardiac muscle. The FHL1 transcript profiles from two affected individuals were investigated in skin fibroblasts with quantitative real-time PCR. This demonstrated loss of isoform A and B, and an almost 200-fold overexpression of isoform C confirming that lack of FHL1A and overexpression of FHL1C results in an extended phenotype of EDMD as recently shown by Tiffin etal. [2013]. © 2015 Elsevier Masson SAS.

Mancini C.,University of Turin | Orsi L.,University of Turin | Guo Y.,Children's Hospital of Philadelphia | Li J.,BGI Shenzhen | And 27 more authors.
BMC Medical Genetics | Year: 2015

Background: Hereditary ataxias are a heterogeneous group of neurodegenerative disorders, where exome sequencing may become an important diagnostic tool to solve clinically or genetically complex cases. Methods: We describe an Italian family in which three sisters were affected by ataxia with postural/intentional myoclonus and involuntary movements at onset, which persisted during the disease. Oculomotor apraxia was absent. Clinical and genetic data did not allow us to exclude autosomal dominant or recessive inheritance and suggest a disease gene. Results: Exome sequencing identified a homozygous c.6292C>T (p.Arg2098*) mutation in SETX and a heterozygous c.346G>A (p.Gly116Arg) mutation in AFG3L2 shared by all three affected individuals. A fourth sister (II.7) had subclinical myoclonic jerks at proximal upper limbs and perioral district, confirmed by electrophysiology, and carried the p.Gly116Arg change. Three siblings were healthy. Conclusions: Exome sequencing is a powerful tool in identifying disease genes. We identified an atypical form of Ataxia with Oculoapraxia type 2 (AOA2) with myoclonus at onset associated with the c.6292C>T (p.Arg2098*) homozygous mutation. Because the same genotype was described in six cases from a Tunisian family with a typical AOA2 without myoclonus, we speculate this latter feature is associated with a second mutated gene, namely AFG3L2 (p.Gly116Arg variant). © Mancini et al.; licensee BioMed Central.

News Article | February 15, 2017
Site: www.eurekalert.org

PHILADELPHIA (February 14, 2017) - Just before Rare Disease Day 2017, a study from the Monell Center and collaborating institutions provides new insight into the causes of trimethylaminura (TMAU), a genetically-transmitted metabolic disorder that leads to accumulation of a chemical that smells like rotting fish. Although TMAU has been attributed solely to mutations in a single gene called FMO3, the new study combined sensory and genetic approaches to identify additional genes that may contribute to TMAU. The findings indicate that genetic testing to identify mutations in the FMO3 gene may not be sufficient to identify the underlying cause of all cases of TMAU. TMAU is classified as a "rare disease," meaning that it affects less than 200,000 people in the United States. However, its actual incidence remains uncertain, due in part to inconclusive diagnostic techniques. "Our findings may bring some reassurance to people who report fish-like odor symptoms but do not have mutations in the FMO3 gene," said Monell behavioral geneticist Danielle R. Reed, PhD, a senior author on the study. The socially and psychologically distressing symptoms of TMAU result from the buildup of trimethylamine (TMA), a chemical compound produced naturally from many foods rich in the dietary constituent, choline. Such foods include eggs, certain legumes, wheat germ, saltwater fish and organ meats. TMA, which has a foul, fishy odor, normally is metabolized by the liver enzyme flavin-containing monooxygenase 3 (FMO3) into an odorless metabolite. People with TMAU are unable to metabolize TMA, presumably due to defects in the underlying FMO3 gene that result in faulty instructions for making functional FMO3 enzymes. The TMA, along with its associated unpleasant odor, then accumulates and is excreted from the body in urine, sweat, saliva, and breath. However, some people who report having the fish odor symptoms of TMAU do not have severely disruptive mutations in the FMO3 gene. This led the researchers to suspect that other genes may also contribute to the disorder. In the new study, reported in the open access journal BMC Medical Genetics, the research team combined a gene sequencing technique known as exome analysis with sophisticated computer modeling to probe for additional TMAU-related genes. The study compared sensory, metabolic and genetic data from ten individuals randomly selected from 130 subjects previously evaluated for TMAU at the Monell Center. Each subject's body odor was evaluated in the laboratory by a trained sensory panel before and after a metabolic test to measure production of TMA over 24 hours following ingestion of a set amount of choline. Although the choline challenge test confirmed a diagnosis of TMAU by revealing a high level of urinary TMA in all 10 subjects, genetic analyses revealed that the FMO3 gene appeared to be normal in four of the 10. Additional analyses revealed defects in several other genes that could contribute to the inability to metabolize the odorous TMA. "We now know that genes other than FMO3 may contribute to TMAU. These new genes may help us better understand the underlying biology of the disorder and perhaps even identify treatments," said Reed. TMAU's odor symptoms may occur in irregular and seemingly unpredictable intervals. This makes the disease difficult to diagnose, as patients can appear to be odor-free when they consult a health professional. This was evidenced in the current study. Although all of the subjects reported frequent fish-odor symptoms, none was judged by the sensory panel to have a fish-like odor at the time of the choline challenge. Monell analytical organic chemist George Preti, PhD, also a senior author, commented on the diagnostic implications of the combined findings, "Regardless of either the current sensory presentation TMAU or the FMO3 genetics, the choline challenge test will confirm the accumulation of TMA that reveals the presence of the disorder." Moving forward, the researchers would like to repeat the genetic analyses in a larger cohort of TMAU patients without FMO3 mutations to confirm which other genes are involved in the disorder. "Such information may identify additional odorants produced by TMAU-positive patients, and inform the future development of gene-based therapies" said Preti. Also contributing to the research were co-lead author Liang-Dar Hwang, Jason Eades, Chung Wen Yu, Corrine Mansfield, Alexis Burdick-Will, and Fujiko Duke of Monell; co-lead author Yiran Guo, Xiao Chang, Brendan Keating, and Hakon Hakonarson of the Center for Applied Genomics at the Children's Hospital of Philadelphia; co-lead author Jiankang Li, Yulan Chen, and Jianguo Zhang of BGI-Shenzhen (China); Steven Fakharzadeh of the Perelman School of Medicine, University of Pennsylvania; Paul Fennessey of the University of Colorado Health Sciences Center; and Hui Jiang of BGI-Shenzhen, the Shenzhen Key Laboratory of Genomics, and the Guangdong Enterprise Key Laboratory of Human Disease Genomics. Funding for the research was provided by the National Organization of Rare Diseases; Institutional funds from the Monell Chemical Center and the Children's Hospital of Philadelphia Research Institute; National Institute on Deafness and Other Communication of the National Institutes of Health (P30DC011735); Shenzhen Municipal Government of China (CXZZ20130517144604091); Shenzhen Key Laboratory of Genomics (CXB200903110066A); and Guangdong Enterprise Key Laboratory of Human Disease Genomics (2011A060906007). Philanthropic funding was provided by the TMAU Foundation, Volatile Analysis, Inc., the family of Mr. and Mrs. Richard Hasselbusch with matching funds from Merck Easy Match, and the late Ms. Bonnie Hunt. The Monell Chemical Senses Center is an independent nonprofit basic research institute based in Philadelphia, Pennsylvania. Poised to celebrate its 50th anniversary in 2018, Monell advances scientific understanding of the mechanisms and functions of taste and smell to benefit human health and well-being. Using an interdisciplinary approach, scientists collaborate in the programmatic areas of sensation and perception; neuroscience and molecular biology; environmental and occupational health; nutrition and appetite; health and well-being; development, aging and regeneration; and chemical ecology and communication. For more information about Monell, visit http://www. .

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