Early prenatal ventriculomegaly due to an AIFM1 mutation identified by linkage analysis and whole exome sequencing.
The identification of disease causing mutation in patients with neurodegenerative disorders originating from small, non-consanguineous families is challenging. Three siblings were found to have ventriculomegaly at early gestation; postnatally, there was no acquisition of developmental milestones, and the muscles of the children were dystrophic. Plasma and CSF lactate levels were normal, but the activities of mitochondrial complex I and IV were markedly decreased. Using linkage analysis in the family, followed by whole exome sequencing of a single patient, we identified a pathogenic mutation in the AIFM1 gene which segregated with the disease state and was absent in 86 anonymous controls. This is the second report of a mutation in the AIFM1 gene, extending the clinical spectrum to include prenatal ventriculomegaly and underscores the importance of AIF for complex I assembly. In summary, linkage analysis followed by exome sequencing of a single patient is a cost-effective approach for the identification of disease causing mutations in small non-consanguineous families.
Monique and Jacques Roboh Department of Genetic Research, Hadassah-Hebrew University Medical Center, Jerusalem, Israel. itberg@hadassah.org.il
Itai
I
Berger
Ziva
Z
Ben-Neriah
Talia
T
Dor-Wolman
Avraham
A
Shaag
Ann
A
Saada
Shamir
S
Zenvirt
Annick
A
Raas-Rothschild
Michel
M
Nadjari
Klaus H
KH
Kaestner
Orly
O
Elpeleg
D000595:Amino Acid Sequence; D051033:Apoptosis Inducing Factor / Q000235:genetics*; D001483:Base Sequence; D017124:Conserved Sequence; D059472:Exome; D017809:Fatal Outcome; D005260:Female; D056726:Genetic Association Studies; D008040:Genetic Linkage; D006239:Haplotypes; D006801:Humans; D006849:Hydrocephalus / Q000000981:diagnostic imaging* / Q000235:genetics; D007231:Infant, Newborn; D008297:Male; D008969:Molecular Sequence Data; D020125:Mutation, Missense; D011247:Pregnancy; D017422:Sequence Analysis, DNA; D016216:Ultrasonography, Prenatal
C494829:AIFM1 protein, human; D051033:Apoptosis Inducing Factor