Association of an X-chromosome dodecamer insertional variant allele with mental retardation.
Mental retardation is a prominent feature of many neurodevelopmental syndromes. In an attempt to identify genetic components of these illnesses, we isolated and sequenced a large number of human genomic cosmid inserts containing large trinucleotide repeats. One of these cosmids, Cos-4, maps to the X-chromosome and contains the sequence of a 7.3-kb mRNA. Initial polymorphism analysis across a region of repetitive DNA in this gene revealed a rare 12-bp exonic variation (<< 1% in non-iII males) having an increased prevalence in non-Fragile X males with mental retardation (4%, P < 0.04, n = 81). This variant was not present in the highly conserved mouse homologue that has 100% amino acid identity to the human sequence near the polymorphism. Subsequent screening of two additional independent cohorts of non-Fragile X mentally retarded patients and ethnically matched controls demonstrated an even higher prevalence of the 12-bp variant in males with mental retardation (8%, P < 0.0003, n = 125, and 14%, P < 0.10, n = 36) vs the controls. Multivariate analysis was conducted in an effort to identify other phenotypic components in affected individuals, and the findings suggested an increased incidence of histories of hypothyroidism (P < 0.001) and treatment with antidepressants (P < 0.001). We conclude that the presence of this 12-bp variant confers significant susceptibility for mental retardation.
Clinical Neuroscience Branch, National Institute of Mental Health, Bethesda, MD 20892, USA. philiber@irp.nimh.nih.gov
R A
RA
Philibert
B H
BH
King
S
S
Winfield
E H
EH
Cook
Y H
YH
Lee
B
B
Stubblefield
P
P
Damschroder-Williams
C
C
Dea
A
A
Palotie
C
C
Tengstrom
B M
BM
Martin
E I
EI
Ginns
D000483:Alleles; D000595:Amino Acid Sequence; D000818:Animals; D001483:Base Sequence; D002140:California / Q000453:epidemiology; D002874:Chromosome Mapping; D017124:Conserved Sequence; D003360:Cosmids; D004251:DNA Transposable Elements; D005060:Europe / Q000453:epidemiology; D005091:Exons; D005260:Female; D005387:Finland / Q000453:epidemiology; D005600:Fragile X Syndrome / Q000235:genetics; D015723:Gene Library; D014644:Genetic Variation; D006801:Humans; D007037:Hypothyroidism / Q000453:epidemiology / Q000235:genetics; D017404:In Situ Hybridization, Fluorescence; D008607:Intellectual Disability / Q000235:genetics*; D008297:Male; D051379:Mice; D008969:Molecular Sequence Data; D011110:Polymorphism, Genetic; D015995:Prevalence; D016415:Sequence Alignment; D017386:Sequence Homology, Amino Acid; D018911:Trinucleotide Repeats; D014960:X Chromosome
D004251:DNA Transposable Elements