Abstract
BackgroundThe prenatal diagnosis of subjects with complete uniparental isodisomy of chromosome 4 (iUPD4) has rarely been reported and poses a great challenge for genetic counseling. In this study, a prenatal case with a high (1 in 58) risk of Down syndrome was diagnosed with iUPD4 by combined chromosomal microarray analysis (CMA), whole exome sequencing (WES) and ultrasound morphology scan.ResultsBy CMA, a pathogenic copy number variant was not detected; however, a complete maternal iUPD4 was identified in this fetus after analyzing the parental genotype results. To detect potentially autosomal recessive variants, WES was performed. Two missense and two frameshift variants were identified but were predicted with uncertain significance; none of the mutations were definitively associated with congenital abnormality or inherited disease. In addition, a detailed ultrasound morphology scan did not identify any structural abnormalities, facial dysmorphisms or intrauterine growth restriction. The family history was unremarkable. The couple was counseled with the prenatal diagnostic results, and they opted to give birth to the child. No phenotypic abnormalities were observed in this child after the first year of life.ConclusionThis study provides further evidence that iUPD4 can result in a healthy live birth and demonstrates that the combined use of CMA, WES and ultrasound technology provides additional information for the prenatal diagnosis and clinical management of rare UPD events.Electronic supplementary materialThe online version of this article (doi:10.1186/s13039-015-0190-z) contains supplementary material, which is available to authorized users.
Highlights
The prenatal diagnosis of subjects with complete uniparental isodisomy of chromosome 4 has rarely been reported and poses a great challenge for genetic counseling
For copy number variations (CNVs) analysis, only a single deletion and a single duplication were identified in the fetal DNA sample, three duplications were found in the mother, and only a single CNV duplication was observed in the father (Fig. 2, Table 1.)
Identification of Uniparental disomy (UPD) events no pathogenic CNVs were identified in either the fetus or his parents, the single-nucleotide polymorphism (SNP) array indicated a complete iUPD of chromosome 4 in the fetus based on the absence of heterozygosity (AOH) across the entire chromosome (Fig. 3a and b)
Summary
The prenatal diagnosis of subjects with complete uniparental isodisomy of chromosome 4 (iUPD4) has rarely been reported and poses a great challenge for genetic counseling. The pathogenesis of UPD is always associated with imprinting disorders or the unmasking of homozygous mutations in iUPD, which can trigger autosomal recessive diseases [6,7,8]. The clinically relevant UPD phenotypes that have been definitively associated with imprinting disorders are limited to regions of 6q24, 7p11.2-p12, 7p32.2, 11p15.5, Liu et al Molecular Cytogenetics (2015) 8:85. Merely relying on ultrasonography data for prenatal genetic counseling makes it challenging to precisely predict which homozygous variations will “activate” recessive mutation events or trigger autosomal recessive disorders in a fetus without obvious dysmorphisms
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