Deletion of chromosome 21 disturbs human brain morphogenesis.
OBJECTIVE
Humans with small deletions of chromosome 21 provide important models for understanding the role of dosage-sensitive genes in brain morphogenesis. To identify chromosome 21 genes responsible for defects of the central nervous system, we determined the deleted regions and brain malformations in three unrelated individuals with overlapping partial deletions of chromosome 21.


METHODS
Fluorescent in situ hybridization and magnetic resonance imaging were used to define the chromosomal structure and structural brain abnormalities present in these three individuals.


RESULTS
The regions of chromosome 21 found to be deleted in these individuals were as follows: case 1: KCNJ6 to the telomere; case 2: ITSN1 to the telomere; and case 3: ITSN1 to PCNT2. The abnormalities of brain structure shared by all included microcephaly, pachygyria, polymicrogyria, colpocephaly, hypoplastic corpus callosum and white matter, hypoplastic cerebellum, and enlarged ventricular system. The clinical features in common included mental retardation, microcephaly, facial dysmorphism, and epilepsy (severe in one patient).


CONCLUSIONS
From analyses of the molecular, cytogenetic, and neuroimaging data from these three individuals, combined with those from previously reported cases, we infer that deletion of an 8.4-Mb region in chromosome band 21q22.2-22.3 (KCNJ6-COL6A2) is associated with cortical dysplasia. We propose that one or more dosage-sensitive genes in this region contributes to cortical development and that deletion of 21q22.2-22.3 should be considered in the diagnosis of mentally retarded patients with facial dysmorphism and cerebral dysplasia.
Yao
Guimei
G
Division of Medical Genetics, Department of Pediatrics, Cedars-Sinai Health System and Department of Human Genetics, University of California at Los Angeles, CA, USA.
Chen
Xiao-Ning
XN
Flores-Sarnat
Laura
L
Barlow
Gillian M
GM
Palka
Giandomenico
G
Moeschler
John B
JB
McGillivray
Barbara
B
Morse
Richard P
RP
Korenberg
Julie R
JR
D000293:Adolescent; D001483:Base Sequence; D001921:Brain / Q000002:abnormalities* / Q000000981:diagnostic imaging / Q000196:embryology; D002675:Child, Preschool; D002872:Chromosome Deletion; D002891:Chromosomes, Human, Pair 21 / Q000235:genetics*; D005260:Female; D018628:Gene Dosage; D006801:Humans; D017403:In Situ Hybridization; D007223:Infant; D008607:Intellectual Disability / Q000000981:diagnostic imaging / Q000235:genetics; D008279:Magnetic Resonance Imaging; D008297:Male; D038081:Organogenesis / Q000235:genetics*; D011859:Radiography