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 Recessive mutations in Middle Eastern families shed light on some U.S. casesBOSTON,  Jan. 23, 2013  /PRNewswire-USNewswire/ -- While autism clearly runs insome families, few inherited genetic causes have been found. A major reason isthat these causes are so varied that it's hard to find enough people with agiven mutation to establish a clear pattern. Researchers at Boston Children'sHospital have pinpointed several inherited mutations-among the first to beidentified-through an unusual approach: using whole-exome sequencing to studylarge Middle Eastern families with autism.The study, published in the  January 23  issue of the journal  Neuron, alsofound evidence for some of the same mutations in U.S. families. It shows that anumber of genes implicated in severe genetic syndromes can have milder mutationsthat primarily cause autism, and could broaden the number of genetic testsavailable to families.Researchers  Tim Yu, MD, PhD,  Maria Chahrour, PhD, and senior investigator Christopher Walsh, MD, PhD, of Boston Children's Hospital, began with threelarge Middle Eastern families that had two or more children with autism spectrumdisorders (ASDs), looking for recessive mutations-those requiring a "double hit"for the child to have an ASD.  "Families from the U.S. are not ideal for finding inherited genetic mutations,since family sizes are often small," says Walsh, chief of Genetics at BostonChildren's and an investigator of the Howard Hughes Medical Institute.  In all three families, the parents were first cousins, a common tradition in the Middle East  and one that greatly facilitates the identification of inheritedmutations. The researchers first used genetic mapping techniques to narrow theirsearch to specific chromosomal locations, then sequenced the protein-codinggenes in those areas (known as whole-exome sequencing).  That turned up recessive mutations in three genes not previously known to beinvolved in autism, but rather in severe genetic syndromes:  * Mutations in  AMT,  a gene classically associated with a severe metabolicsyndrome known as nonketotic hyperglycinemia, marked by severe seizures anddeath during infancy.  * Mutations in  PEX7. Typical  PEX7  mutations cause rhizomelic chondrodysplasiapunctata, a severe syndrome causing metabolic and bone abnormalities, cataracts,severe epilepsy and early death.  * Mutations in  SYNE1, a gene associated with brain malformation, severe motorand muscle problems, and possibly bipolar psychiatric disease.  The severe syndromes linked to these genes often include autistic behavior orintellectual disability, but not as the primary symptom. Interestingly, themilder mutations discovered in these families seemed to cause disease that ismore brain-specific."This is the first time these genes have been associated with autism," saysChahrour, who shares first authorship of the study with Yu. "The  AMT  and  PEX7 mutations weren't picked up by standard tests for metabolic disorders, but whenyou're able to sequence the entire exome, you can find them."These findings inspired the team to look for other metabolic and other geneticsyndromes affecting cognition and behavior with milder forms showing up simplyas autism. They screened 163 Middle Eastern families with autism for mutationsin 70 genes associated with these syndromes, using a whole-exome approach butanalyzing only the 70 genes of interest.  This approach turned up several additional families with ASD mutations,including:  * An additional family with a recessive mutation in  AMT* Two families with recessive mutations in  VPS13B  (known to cause Cohensyndrome, which includes intellectual disability, obesity, vision and jointproblems, and small head size)  * A family with a recessive mutation in  POMGNT1  (known to causemuscle-eye-brain disease, marked by brain malformation, intellectual disability,muscle and vision problems)  * A family with an X-linked mutation in  MECP2  in two boys (MECP2  mutationsare known to cause Rett syndrome in girls, but are typically lethal in boys)  "We have textbook descriptions of all these diseases, but in real life, therecan be atypical, milder presentations of the same disease," says Yu. "The kidswe were studying with autism were alive at age 13. They had double hits forthese mutations, but they were much milder mutations. The proteins retained abit of their function."The team also examined a cohort of U.S. patients, looking for recessivemutations in six of the genes they identified. They analyzed whole-exomesequence data from 612 families with ASDs, part of a registry known as theSimons Simplex Collection.  The analysis suggested that some of the affectedchildren had causative recessive mutations in at least two of the genesidentified in the Middle Eastern families, and that larger-scale efforts toexamine all 70 genes more fully for recessive mutations may prove fruitful.    "It's not clear yet how many U.S. families have these recessive mutations," saysYu. "Further studies could begin to estimate what fraction of autism cases mightfall under this model."The Boston Children's study complements another study published in the sameissue of Neuron, led by Dr.  Mark Daly  of Massachusetts General Hospital andthe Broad Institute. That study looked for recessive mutations across the entiregenome in 933 cases and 869 controls-but specifically sought those thatcompletely abolished a gene's function."Together, these two studies firmly establish that recessive mutationscontribute importantly to autism, not just in specialized populations but in thepopulation at large," says Yu. "Genome sequencing is going to be a huge advancein identifying more of these mutations, since there are a lot of rare syndromesthat are otherwise very difficult to detect."      Major funding for the Boston Children's study was provided by the NationalInstitutes of Health (T32 NS007484-08), the National Institute of Mental Health(RO1 MH083565; 1RC2MH089952), the Nancy Lurie Marks Foundation, the SimonsFoundation, the Autism Consortium, the Manton Center for Autism Disease Researchand the Howard Hughes Medical Institute.Boston Children's Hospital is home to the world's largest research enterprisebased at a pediatric medical center, where its discoveries have benefited bothchildren and adults since 1869. More than 1,100 scientists, including ninemembers of the National Academy of Sciences, 11 members of the Institute ofMedicine and 12 members of the Howard Hughes Medical Institute comprise BostonChildren's research community. Founded as a 20-bed hospital for children, BostonChildren's today is a 395-bed comprehensive center for pediatric and adolescenthealth care grounded in the values of excellence in patient care and sensitivityto the complex needs and diversity of children and families. Boston Children'salso is a teaching affiliate of  Harvard Medical School. For more informationabout research and clinical innovation at Boston Children's, visit: 
  http://vectorblog.org/.
 CONTACT:Keri StedmanBoston Children's Hospital617-919-3110keri.stedman@childrens.harvard.eduSOURCE  Boston Children's Hospital