title: Uniparental disomy of chromosome 8 leading to homozygosity of a CYP11B1 mutation in a patient with congenital adrenal hyperplasia: implication for a rare etiology of an autosomal recessive disorder.
abstract: Congenital adrenal hyperplasia (CAH) is an autosomal recessive disorder that usually results from paternally and maternally transmitted mutations in genes for steroidogenic enzymes. Recent studies on steroid 21-hydroxylase deficiency, the most common form of CAH, have revealed that a small percentage of patients have a non-carrier parent; uniparental disomy (UPD) and de novo mutations were reported as disease-causing mechanisms in these patients. However, it remains unknown whether UPD and de novo mutations underlie other forms of CAH. Here, we report a male patient with steroid 11β-hydroxylase deficiency (11OHD) born to a non-carrier mother. The patient was identified by an elevated 17-hydroxyprogesterone level at a neonatal mass-screening test. His clinical features were comparable to those of previously reported patients with 11OHD. Direct sequencing of CYP11B1 identified a homozygous IVS7+1G>A mutation in the patient, which was not shared by his mother. Comparative genomic hybridization of the patient detected UPD of chromosome 8 [UPD(8)]. Microsatellite analysis indicated non-maternal origin of the UPD(8) and confirmed parentage of other chromosomes. This study shows for the first time that 11OHD can be caused by UPD in the presence of a non-carrier parent. Awareness of such rare cases should improve the accuracy of genetic counseling for families with CAH. Our data support the importance of UPD as an underlying mechanism of autosomal recessive disorders.
authors.affiliation: Department of Molecular Endocrinology, National Research Institute for Child Health and Development, Tokyo 157-8535, Japan.
authors.forename: Keiko
authors.initials: K
authors.lastname: Matsubara
authors.forename: Naoki
authors.initials: N
authors.lastname: Kataoka
authors.forename: Satoko
authors.initials: S
authors.lastname: Ogita
authors.forename: Shinichiro
authors.initials: S
authors.lastname: Sano
authors.forename: Tsutomu
authors.initials: T
authors.lastname: Ogata
authors.forename: Maki
authors.initials: M
authors.lastname: Fukami
authors.forename: Noriyuki
authors.initials: N
authors.lastname: Katsumata
mesh_terms: D000312:Adrenal Hyperplasia, Congenital / Q000235:genetics*; D000328:Adult; D002898:Chromosomes, Human, Pair 8 / Q000235:genetics*; D005260:Female; D005808:Genes, Recessive; D006720:Homozygote; D006801:Humans; D007231:Infant, Newborn; D008297:Male; D009154:Mutation; D013252:Steroid 11-beta-Hydroxylase / Q000235:genetics*; D024182:Uniparental Disomy / Q000235:genetics
chemical_list: D013252:Steroid 11-beta-Hydroxylase