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Genomics In The Journals: Jul 21, 2011

By a GenomeWeb staff reporter

NEW YORK (GenomeWeb News) – Researchers looking for variants involved in attention-deficit hyperactivity disorder inadvertently identified mutations causing the blood condition idiopathic hemolytic anemia in one of their research subjects — findings they reported in Discovery Medicine. The international team did whole-exome sequencing on members of an ADHD-affected family from Utah. Though they're still searching for variants explaining the severe ADHD seen in the father of this family and his two sons, the team did determine that one of the men carries anemia-causing mutations in the pyruvate kinase enzyme coding gene PKLR — unanticipated findings that they relayed to the man's doctor.

Three independent studies in Nature Genetics have found that mutations in NBEAL2, a neurobeachin-like 2 gene on chromosome 3, can cause another blood disorder: a recessive bleeding condition known as gray platelet syndrome.

Researchers from the UK, France, and the Netherlands found NBEAL2 mutations through whole-exome sequencing on four unrelated individuals with gray platelet syndrome. After capturing coding sequences with the Agilent SureSelect system, sequencing these exons with the Illumina GAII, and filtering genetic variants in the exomes, the group found that all of the patients tested carried NBEAL2 mutations.

An American and Israeli-led team found NBEAL2 mutations in 15 unrelated individuals with gray platelet syndrome when they did Sanger sequencing on some exons that had been missed in earlier exome sequencing experiments. That team also found gray platelet syndrome-related differences in the NBEAL2 transcripts that individuals express.

A third research team, from Canada and the US, detected NBEAL2 mutations using genome-wide RNA sequencing of platelet-derived messenger RNA from one individual with gray platelet syndrome, followed by DNA sequencing of the gene in that individual and several others with the blood condition.

Testing for mutations in the GNAS gene may determine which pancreatic cysts are most likely to progress to cancer, according to a Science Translational Medicine study. A Johns Hopkins University-led team sequenced the coding exons of 169 oncogenes and tumor suppressor genes in cyst fluid samples from 19 individuals with "intraductal papillary mucinous neoplasm" (IPMN) cysts. Along with recurrent mutations in KRAS, a gene previously linked to pancreatic cancer, the team found mutations affecting the same GNAS codon in six of the 19 pre-cancerous cyst samples. When they tested 132 more IPMN cysts and a handful of invasive pancreatic ductal adenocarcinoma (PDA) cancers stemming from these cysts, the researchers found GNAS mutations in nearly two-thirds of the pre-cancerous cysts and in seven of the eight cancers. On the other hand, they did not see GNAS mutations in benign or less cancer-prone pancreatic cysts or in invasive PDAs that were not preceded by IPMN cysts.

"In addition to defining a new pathway for pancreatic neoplasia, these data suggest that GNAS mutations can inform the diagnosis and management of patients with cystic pancreatic lesions," corresponding author Bert Vogelstein, co-director of Johns Hopkins' Ludwig Center, and his co-authors wrote.

In the American Journal of Human Genetics, American, Italian, and Turkish researchers describe how they used whole-exome sequencing to find mutations behind KBG syndrome, a genetic condition characterized by specific tooth, skull, and facial features, as well as other skeletal changes and intellectual disability. After identifying mutations in the ankyrin repeat domain 11 gene ANKRD11 in three affected individuals from two families using targeted sequence capture with the Roche EZ Exome v2.0 kit and the Illumina GAIIx sequencing platform, the team sequenced the gene in members of these families and eight other KBG-affected families. ANKRD11 mutations turned up in half of the families tested, they report, suggesting the gene is behind some, but probably not all, KBG cases.

"[O]ur results indicate that ANKRD11 mutations are a cause of KBG syndrome and delineate a fundamental role of ANKRD11 in craniofacial, dental, skeletal, and central nervous system development and function," senior author Mustafa Tekin, a researcher affiliated with the University of Miami and Ankara University School of Medicine in Turkey, and co-authors wrote. "Further studies are warranted to identify other genetic defects of this genetically heterogeneous condition."

University of North Carolina at Chapel Hill researchers report in Science that they have found two new cytosine derivatives — 5-formylcytosine (5fC) and 5-carboxylcytosine (5caC) — generated from a methylated form of the cytosine nucleotide called 5-methylcytosine (5mC). Their follow-up experiments suggest these modified cytosine bases are produced during DNA demethylation by Tet proteins, the same enzymes that help turn 5mC into 5-hydroxymethylcytosine. The researchers also detected both 5fC and 5caC in DNA isolated from mouse embryonic stem cells and tissue samples, though they say more research is needed to figure out how the bases operate in the genome.

"Before we can grasp the magnitude of this discovery, we have to figure out the function of these new bases," senior author Yi Zhang, a biochemistry and biophysics researcher at UNC, said in a statement. "Because these bases represent an intermediate state in the demethylation process, they could be important for cell fate reprogramming and cancer, both of which involve DNA demethylation."

Also in Science, authors of a study published last July on genetic signatures for longevity have issued a retraction of the paper, citing technical errors in the array used and quality control problems. The retraction comes on the heels of an "editorial expression of concern" about the paper in Science last November. Although they say new analyses support the main conclusions of their longevity study, the Italian and American authors say they "retract the original manuscript and will pursue alternative publication of the new findings."

Genomics In The Journals is a weekly feature pointing readers to select, recently published articles involving genomics and related research.

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