title: Identifying autism loci and genes by tracing recent shared ancestry.
abstract: To find inherited causes of autism-spectrum disorders, we studied families in which parents share ancestors, enhancing the role of inherited factors. We mapped several loci, some containing large, inherited, homozygous deletions that are likely mutations. The largest deletions implicated genes, including PCDH10 (protocadherin 10) and DIA1 (deleted in autism1, or c3orf58), whose level of expression changes in response to neuronal activity, a marker of genes involved in synaptic changes that underlie learning. A subset of genes, including NHE9 (Na+/H+ exchanger 9), showed additional potential mutations in patients with unrelated parents. Our findings highlight the utility of "homozygosity mapping" in heterogeneous disorders like autism but also suggest that defective regulation of gene expression after neural activity may be a mechanism common to seemingly diverse autism mutations.
authors.affiliation: Division of Genetics, Children's Hospital Boston and Harvard Medical School, Boston, MA 02115, USA.
authors.forename: Eric M
authors.initials: EM
authors.lastname: Morrow
authors.forename: Seung-Yun
authors.initials: SY
authors.lastname: Yoo
authors.forename: Steven W
authors.initials: SW
authors.lastname: Flavell
authors.forename: Tae-Kyung
authors.initials: TK
authors.lastname: Kim
authors.forename: Yingxi
authors.initials: Y
authors.lastname: Lin
authors.forename: Robert Sean
authors.initials: RS
authors.lastname: Hill
authors.forename: Nahit M
authors.initials: NM
authors.lastname: Mukaddes
authors.forename: Soher
authors.initials: S
authors.lastname: Balkhy
authors.forename: Generoso
authors.initials: G
authors.lastname: Gascon
authors.forename: Asif
authors.initials: A
authors.lastname: Hashmi
authors.forename: Samira
authors.initials: S
authors.lastname: Al-Saad
authors.forename: Janice
authors.initials: J
authors.lastname: Ware
authors.forename: Robert M
authors.initials: RM
authors.lastname: Joseph
authors.forename: Rachel
authors.initials: R
authors.lastname: Greenblatt
authors.forename: Danielle
authors.initials: D
authors.lastname: Gleason
authors.forename: Julia A
authors.initials: JA
authors.lastname: Ertelt
authors.forename: Kira A
authors.initials: KA
authors.lastname: Apse
authors.forename: Adria
authors.initials: A
authors.lastname: Bodell
authors.forename: Jennifer N
authors.initials: JN
authors.lastname: Partlow
authors.forename: Brenda
authors.initials: B
authors.lastname: Barry
authors.forename: Hui
authors.initials: H
authors.lastname: Yao
authors.forename: Kyriacos
authors.initials: K
authors.lastname: Markianos
authors.forename: Russell J
authors.initials: RJ
authors.lastname: Ferland
authors.forename: Michael E
authors.initials: ME
authors.lastname: Greenberg
authors.forename: Christopher A
authors.initials: CA
authors.lastname: Walsh
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000235:genetics; D000818:Animals; D001321:Autistic Disorder / Q000235:genetics* / Q000503:physiopathology; D001921:Brain / Q000378:metabolism; D015820:Cadherins / Q000235:genetics; D002874:Chromosome Mapping; D003241:Consanguinity; D005260:Female; D000080865:Formins; D017353:Gene Deletion; D018628:Gene Dosage; D005786:Gene Expression Regulation; D005808:Genes, Recessive; D020022:Genetic Predisposition to Disease; D006720:Homozygote; D006801:Humans; D008126:Lod Score; D008297:Male; D009154:Mutation; D009474:Neurons / Q000502:physiology; D020411:Oligonucleotide Array Sequence Analysis; D010375:Pedigree; D020641:Polymorphism, Single Nucleotide; D000091363:Protocadherins; D051381:Rats; D017923:Sodium-Hydrogen Exchangers / Q000235:genetics; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D015820:Cadherins; C108962:DIAPH1 protein, human; D000080865:Formins; C438603:PCDH10 protein, human; D000091363:Protocadherins; C478541:SLC9A9 protein, human; D017923:Sodium-Hydrogen Exchangers; D014157:Transcription Factors