RESUMO
OBJECTIVE: To delineate the significance of maternal uniparental disomy 14 (upd(14)mat) and related disorders in patients with a Prader-Willi syndrome (PWS)-like phenotype. STUDY DESIGN: We examined 78 patients with PWS-like phenotype who lacked molecular defects for PWS. The MEG3 methylation test followed by microsatellite polymorphism analysis of chromosome 14 was performed to detect upd(14)mat or other related abnormalities affecting the 14q32.2-imprinted region. RESULTS: We identified 4 patients with upd(14)mat and 1 patient with an epimutation in the 14q32.2 imprinted region. Of the 4 patients with upd(14)mat, 3 had full upd(14)mat and 1 was mosaic. CONCLUSIONS: Upd(14)mat and epimutation of 14q32.2 represent clinically discernible phenotypes and should be designated "upd(14)mat syndrome." This syndrome demonstrates a PWS-like phenotype particularly during infancy. The MEG3 methylation test can detect upd(14)mat syndrome defects and should therefore be performed for all undiagnosed infants with hypotonia.
Assuntos
Cromossomos Humanos Par 14/genética , Fenótipo , Síndrome de Prader-Willi/diagnóstico , Síndrome de Prader-Willi/genética , Dissomia Uniparental/diagnóstico , Dissomia Uniparental/genética , Adolescente , Adulto , Criança , Pré-Escolar , Estudos de Coortes , Feminino , Humanos , Lactente , Masculino , Regiões Promotoras Genéticas/genética , Proteínas/genética , RNA Longo não Codificante , Síndrome , Adulto JovemRESUMO
OBJECTIVE: To characterize inheritance of homozygous, rare, recessive loss-of-function mutations in surfactant protein-B (SFTPB) or ATP binding cassette, subfamily A, member 3 (ABCA3) genes in newborns with lethal respiratory failure. STUDY DESIGN: We resequenced genes from parents whose infants were homozygous for mutations in SFTPB or ABCA3. For infants with only 1 heterozygous parent, we performed microsatellite analysis for chromosomes 2 (SFTPB) and 16 (ABCA3). RESULTS: We identified 1 infant homozygous for the g.1549C > GAA mutation (121ins2) in SFTPB for whom only the mother was heterozygous and 3 infants homozygous for mutations in ABCA3 (p.K914R, p.P147L, and c.806_7insGCT) for whom only the fathers were heterozygous. For the SP-B-deficient infant, microsatellite markers confirmed maternal heterodisomy with segmental isodisomy. Microsatellite analysis confirmed paternal isodisomy for the 3 ABCA3-deficient infants. Two ABCA3-deficient infants underwent lung transplantation at 3 and 5 months of age, respectively, and 2 infants died. None exhibited any nonpulmonary phenotype. CONCLUSIONS: Uniparental disomy should be suspected in infants with rare homozygous mutations in SFTPB or ABCA3. Confirmation of parental carrier status is important to provide recurrence risk and to monitor expression of other phenotypes that may emerge through reduction to homozygosity of recessive alleles.