Identifying autism loci and genes by tracing recent shared ancestry.
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.
Morrow
Eric M
EM
Division of Genetics, Children's Hospital Boston and Harvard Medical School, Boston, MA 02115, USA.
Yoo
Seung-Yun
SY
Flavell
Steven W
SW
Kim
Tae-Kyung
TK
Lin
Yingxi
Y
Hill
Robert Sean
RS
Mukaddes
Nahit M
NM
Balkhy
Soher
S
Gascon
Generoso
G
Hashmi
Asif
A
Al-Saad
Samira
S
Ware
Janice
J
Joseph
Robert M
RM
Greenblatt
Rachel
R
Gleason
Danielle
D
Ertelt
Julia A
JA
Apse
Kira A
KA
Bodell
Adria
A
Partlow
Jennifer N
JN
Barry
Brenda
B
Yao
Hui
H
Markianos
Kyriacos
K
Ferland
Russell J
RJ
Greenberg
Michael E
ME
Walsh
Christopher A
CA
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
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