Prenatal detection of mosaicism for a genome wide uniparental disomy cell line in a cohort of patients: Implications and outcomes.

OBJECTIVES: To investigate the prenatal detection rate of mosaicism by SNP microarray analysis, in which an individual has not one, but two, complete genomes (sets of DNA) in their body, a normal biparental line with a Genome Wide Uniparental Disomy (GWUPD) cell line was used. METHODS: This study retrospectively examines the prenatal detection of GWUPD in a cohort of ∼90,000 prenatal specimens and ∼20,000 products of conceptions (POCs) that were studied by SNP microarray. RESULTS: In total, 25 cases of GWUPD were detected; 16 cases were detected prenatally with GWUPD (∼0.018%) and 9 POCs revealed GWUPD (0.045%). The nine POC specimens presented with placental abnormalities. The 12 amniotic fluid specimens were ascertained because of abnormal ultrasound findings. Nine of 12 pregnancies had findings consistent with Beckwith-Wiedemann syndrome or because of abnormal placentas. However, three pregnancies were detected with GWUPD of maternal origin, with less common findings and demonstrated maternal origin. Four other pregnancies showed GWUPD in a chorionic villus sample, but normal findings in amniotic fluid and apparently normal fetal development. CONCLUSIONS: This cohort with GWUPD mosaicism expands our understanding of GWUPD and has implications for prenatal care and counseling. Additional studies are necessary to understand the rarer maternal GWUPD.

A prenatal diagnosis of mosaic trisomy 5 reveals a postnatal complete uniparental disomy of chromosome 5 with multiple congenital anomalies.

Mosaic trisomy 5 is a very rare condition in liveborns, with few cases reported in the last four decades. There are some reports of prenatally diagnosed mosaic trisomy 5 resulting in phenotypically normal offspring, suggesting a low level of mosaicism, but there are also reports associated with multiple congenital anomalies, cardiovascular malformations, and intrauterine growth restriction. We report an infant male diagnosed with mosaic trisomy 5 (5/15 cells) via amniocentesis. The patient was subsequently found to have uniparental disomy 5 (UPD5) by postnatal chromosome microarray, but high-resolution chromosome analysis on peripheral blood did not identify trisomy 5. Dysmorphic features included a tall forehead with low anterior hairline, hypertelorism, low-set ears, and a prominent nose and midface. Other anomalies included bilateral bifid thumbs, hypospadias, a perineal fistula, unilateral multicystic kidney, and decreased subcutaneous fat with loose skin. He had complex congenital heart disease consisting of ventricular and atrial septal defects and polyvalvular defects. The patient died at age one after a prolonged admission. We add this case to the literature with the added benefit of data from a postnatal microarray, which was not available in other cases, to broaden the phenotype of mosaic trisomy 5 and UPD5.With the current available technology, we stress the importance of postnatal genetic testing to confirm prenatal cytogenetic findings in order to further define such phenotypes. This will provide the most accurate information and counseling to affected families.

Chromosomal microarray analysis in clinical evaluation of neurodevelopmental disorders-reporting a novel deletion of SETDB1 and illustration of counseling challenge.

BACKGROUND: The pathogenicity of copy number variations (CNV) in neurodevelopmental disorders is supported by research literature. However, few studies have evaluated the utility and counseling challenges of CNV analysis in clinic. METHODS: We analyzed the findings of CNV studies from a cohort referred for genetics evaluation of autism spectrum disorders (ASD), developmental disability (DD), and intellectual disability (ID). RESULTS: Twenty-two CNV in 21 out of 115 probands are considered to be pathogenic (18.3%). Five CNV are likely pathogenic and 22 CNV are variants of unknown significance (VUS). We have found seven cases with more than two CNV and two with a complex rearrangement of the 22q13.3 Phelan-McDermid syndrome region. We identified a new and de novo 1q21.3 deletion that encompasses SETDB1, a gene encoding methylates histone H3 on lysine-9 (H3K9) methyltransferase, in a case with ASD. CONCLUSION: We provide evidence to support the value of CNV analysis in etiological evaluation of neurodevelopmental disorders in autism genetics clinic. However, interpretation of the clinical significance and counseling families are still challenging because of the variable penetrance and pleotropic expressivity of CNV. In addition, the identification of a 1q21.3 deletion encompassing SETDB1 provides further support for the role of chromatin modifiers in the etiology of ASD.

Three cases of isolated terminal deletion of chromosome 8p without heart defects presenting with a mild phenotype.

Individuals with isolated terminal deletions of 8p have been well described in the literature, however, molecular characterization, particularly by microarray, of the deletion in most instances is lacking. The phenotype of such individuals falls primarily into two categories: those with cardiac defects, and those without. The architecture of 8p has been demonstrated to contain two inversely oriented segmental duplications at 8p23.1, flanking the gene, GATA4. Haploinsufficiency of this gene has been implicated in cardiac defects seen in numerous individuals with terminal 8p deletion. Current microarray technologies allow for the precise elucidation of the size and gene content of the deleted region. We present three individuals with isolated terminal deletion of 8p distal to the segmental duplication telomeric to GATA4. These individuals present with a relatively mild and nonspecific phenotype including mildly dysmorphic features, developmental delay, speech delay, and early behavior issues.

Phenotypic heterogeneity in a family with a small atypical microduplication of chromosome 22q11.2 involving TBX1.

The chromosome 22q11.2 region is commonly involved in non-allelic homologous recombination (NAHR) events. Microduplications of 22q11.2, usually involving a 3 Mb or 1.5 Mb region constitute the 22q11 microduplication syndrome. Both microdeletions and microduplications of 22q11.21 are reported to share several phenotypic characteristics, including dysmorphic facial features, velopharyngeal insufficiency, congenital heart disease, urogenital abnormalities, and immunologic defects. We report a child who presented at 8 months of age for evaluation of microcephaly and mild motor delay. Head circumference at birth, at 8 months, and at 19 months of age was below the 3rd centile. Other findings included left-sided cryptorchidism and developmental dysplasia of the left hip. In addition, echocardiography revealed a restrictive patent ductus arteriosus. Chromosomal microarray analysis using Affymetrix Genome-Wide Human SNP Array 6.0 revealed a novel 437 kb interstitial duplication at 22q11.21, involving TBX1, whose breakpoints did not coincide with known low copy repeat (LCR) regions. The same duplication was confirmed by fluorescent in situ hybridization (FISH) in the patient's mother and an older sister. The mother has a history of anxiety disorder and depression. The sister had a history of delayed motor milestones. None of the three duplication carriers has any documented renal anomalies or other significant medical problems. This report demonstrates the clinical heterogeneity associated with microduplications of 22q11.2 and illustrates the difficulties related to providing prognostic information and accurate genetic counseling to families when this finding is detected. The described microduplication is the smallest in this genomic region reported to date and further implicates abnormal gene dosage of TBX1 in disorders resulting from 22q11.2 rearrangements.

Microdeletion/microduplication of proximal 15q11.2 between BP1 and BP2: a susceptibility region for neurological dysfunction including developmental and language delay.

The proximal long arm of chromosome 15 has segmental duplications located at breakpoints BP1-BP5 that mediate the generation of NAHR-related microdeletions and microduplications. The classical Prader-Willi/Angelman syndrome deletion is flanked by either of the proximal BP1 or BP2 breakpoints and the distal BP3 breakpoint. The larger Type I deletions are flanked by BP1 and BP3 in both Prader-Willi and Angelman syndrome subjects. Those with this deletion are reported to have a more severe phenotype than individuals with either Type II deletions (BP2-BP3) or uniparental disomy 15. The BP1-BP2 region spans approximately 500 kb and contains four evolutionarily conserved genes that are not imprinted. Reports of mutations or disturbed expression of these genes appear to impact behavioral and neurological function in affected individuals. Recently, reports of deletions and duplications flanked by BP1 and BP2 suggest an association with speech and motor delays, behavioral problems, seizures, and autism. We present a large cohort of subjects with copy number alteration of BP1 to BP2 with common phenotypic features. These include autism, developmental delay, motor and language delays, and behavioral problems, which were present in both cytogenetic groups. Parental studies demonstrated phenotypically normal carriers in several instances, and mildly affected carriers in others, complicating phenotypic association and/or causality. Possible explanations for these results include reduced penetrance, altered gene dosage on a particular genetic background, or a susceptibility region as reported for other areas of the genome implicated in autism and behavior disturbances.