title: Microdeletion of the Down syndrome critical region at 21q22.
abstract: The concept of the Down syndrome critical region implies the existence of several dosage-sensitive genes that result in an abnormal phenotype when duplicated. Among the genes in the presumed Down syndrome critical region, DYRK1A and SIM2 are thought to be particularly important because of their critical roles in the development of the central nervous system in model organisms. Considering that regulatory imbalances resulting in an altered amount of expression from crucial target genes tend to produce phenotypic effects in both monosomics and trisomics, haploinsufficiency for the Down syndrome critical region is expected to be associated with an abnormal phenotype. We report on a patient with severe microcephaly, a developmental delay, hypospadias, and corneal opacity who had a microdeletion spanning the Down syndrome critical region, including DYRK1A and SIM2. He presented with intrauterine growth retardation, hypospadias, corneal clouding, arched eyebrows, upslanting and narrow palpebral fissures, bifid uvula, prominent nasal root, short columella, prominent central incisors, pegged shaped teeth, retrognathia, hypoplastic nipples, and severe developmental delay. His G-banded karyotype was normal, but array comparative genomic hybridization showed a de novo deletion of 3.97 Mb at chromosome 21q22. The extreme degree of microcephaly in this patient may be ascribed to the haploinsufficiency of DYRK1A, since brain size is severely reduced in heterozygotes for the Dyrk1a null mutation in mice.
authors.affiliation: Division of Clinical Genetics and Molecular Medicine, National Center for Child Health and Development, Tokyo, Japan.
authors.forename: Hideki
authors.initials: H
authors.lastname: Fujita
authors.forename: Chiharu
authors.initials: C
authors.lastname: Torii
authors.forename: Rika
authors.initials: R
authors.lastname: Kosaki
authors.forename: Shinya
authors.initials: S
authors.lastname: Yamaguchi
authors.forename: Jun
authors.initials: J
authors.lastname: Kudoh
authors.forename: Kumiko
authors.initials: K
authors.lastname: Hayashi
authors.forename: Takao
authors.initials: T
authors.lastname: Takahashi
authors.forename: Kenjiro
authors.initials: K
authors.lastname: Kosaki
mesh_terms: D002648:Child; D002675:Child, Preschool; D002872:Chromosome Deletion; D002891:Chromosomes, Human, Pair 21 / Q000235:genetics*; D055028:Comparative Genomic Hybridization; D004314:Down Syndrome / Q000235:genetics*; D019066:Facies; D005260:Female; D006801:Humans; D017404:In Situ Hybridization, Fluorescence; D007223:Infant; D007231:Infant, Newborn; D008297:Male; D011247:Pregnancy; D015203:Reproducibility of Results