Enrichment of small pathogenic deletions at chromosome 9p24.3 and 9q34.3 involving DOCK8, KANK1, EHMT1 genes identified by using high-resolution oligonucleotide-single nucleotide polymorphism array analysis.

BACKGROUND: High-resolution oligo-SNP array allowed the identification of extremely small pathogenic deletions at numerous clinically relevant regions. In our clinical practice, we found that small pathogenic deletions were frequently encountered at chromosome 9p and 9q terminal regions. RESULTS: A review of 531 cases with reportable copy number changes on chromosome 9 revealed142 pathogenic copy number variants (CNVs): 104 losses, 31 gains, 7 complex chromosomal rearrangements. Of 104 pathogenic losses, 57 were less than 1 Mb in size, enriched at 9p24.3 and 9q34.3 regions, involving the DOCK8, KANK1, EHMT1 genes. The remaining 47 cases were due to interstitial or terminal deletions larger than 1 Mb or unbalanced translocations. The small pathogenic deletions of DOCK8, KANK1 and EHMT1 genes were more prevalent than small pathogenic deletions of NRXN1, DMD, SHANK3 genes and were only second to the 16p11.2 deletion syndrome, 593-kb (OMIM #611913). CONCLUSIONS: This study corroborated comprehensive genotype-phenotype large scale studies at 9p24.3 and 9q24.3 regions for a better understanding of the pathogenicity caused by haploinsufficiency of the DOCK8, KANK1 and EHMT1 genes. TRIAL REGISTRATION NUMBER: None; it is not a clinical trial, and the cases were retrospectively collected and analyzed.

Mosaic trisomy 15 in a liveborn infant.

With only a small number of cases in the medical literature, mosaic trisomy 15 in liveborn infants is very rare. Despite its rarity, similar features among individuals have been described, including intrauterine growth retardation, craniofacial abnormalities and facial dysmorphisms, cardiac disease, and other organ anomalies. Very few liveborns have survived the first year of life. We report here on a term infant with growth restriction and multiple congenital anomalies who was found to have mosaic trisomy 15. The proband presented with some frequently reported findings such as dysmorphic facies and overlapping fingers, and the uncommon finding of whorled hypopigmentation. Previously unreported findings include abnormal cerebral vasculature and dysplastic kidneys. We add this new phenotypic information to widen the spectrum previously reported and provide a review of the literature to date.

Concurrent triplication and uniparental isodisomy: evidence for microhomology-mediated break-induced replication model for genomic rearrangements.

Whole-genome oligonucleotide single-nucleotide polymorphism (oligo-SNP) arrays enable simultaneous interrogation of copy number variations (CNVs), copy neutral regions of homozygosity (ROH) and uniparental disomy (UPD). Structural variation in the human genome contributes significantly to genetic variation, and often has deleterious effects leading to disease causation. Co-occurrence of CNV and regions of allelic homozygosity in tandem involving the same chromosomal arm are extremely rare. Replication-based mechanisms such as microhomology-mediated break-induced replication (MMBIR) are recent models predicted to induce structural rearrangements and gene dosage aberrations; however, supportive evidence in humans for one-ended DNA break repair coupled with MMBIR giving rise to interstitial copy number gains and distal loss of heterozygosity has not been documented. We report on the identification and characterization of two cases with interstitial triplication followed by uniparental isodisomy (isoUPD) for remainder of the chromosomal arm. Case 1 has a triplication at 9q21.11-q21.33 and segmental paternal isoUPD for 9q21.33-qter, and presented with citrullinemia with a homozygous mutation in the argininosuccinate synthetase gene (ASS1 at 9q34.1). Case 2 has a triplication at 22q12.1-q12.2 and segmental maternal isoUPD 22q12.2-qter, and presented with hearing loss, mild dysmorphic features and bilateral iris coloboma. Interstitial triplication coupled with distal segmental isoUPD is a novel finding that provides human evidence for one-ended DNA break and replication-mediated repair. Both copy number gains and isoUPD may contribute to the phenotype. Significantly, these cases represent the first detailed genomic analysis that provides support for a MMBIR mechanism inducing copy number gains and segmental isoUPD in tandem.

Abnormalities in spontaneous abortions detected by G-banding and chromosomal microarray analysis (CMA) at a national reference laboratory.

BACKGROUND: Cytogenetic evaluation of products of conception (POC) for chromosomal abnormalities is central to determining the cause of pregnancy loss. We compared the test success rates in various specimen types and the frequencies of chromosomal abnormalities detected by G-banding analysis with those found by Oligo-SNP chromosomal microarray analysis (CMA). We evaluated the benefit of CMA testing in cases of failed culture growth. METHODS: Conventional cytogenetic results of 5457 consecutive POC specimens were reviewed and categorized as placental villi, fetal parts, and unspecified POC tissue. The CMA was performed on 268 cases. Of those, 32 cases had concurrent G-banding results. The remaining 236 cases included 107 cases with culture failure and 129 cases evaluated by CMA alone. RESULTS: The overall POC culture success rate was 75%, with the lowest for fetal parts (37.4%) and the highest for placental villi (81%). The abnormality rate was 58% for placental villi, but only 25% for fetal parts. Of the abnormalities detected, the most common were aneuploidies, including trisomy 16, triploidy, monosomy X, trisomy 22, trisomy 21 and trisomy 15, while the least encountered aneuploidies were trisomy 1, trisomy 19 and monosomies (except monosomy 21). Overall, POC specimens studied by CMA were successful in 89.6% of cases and yielded a 44.6% abnormality rate. CONCLUSIONS: Placental villi yielded higher rates of culture success and a higher percentage of abnormal karyotypes than did other specimen types. The Oligo-SNP CMA method has demonstrated a viable alternative to the G-banding method in view of its advantages in detection of submicroscopic genomic aberrations, shorter turnaround time due to elimination of time required for culture and a higher test success rate.

Inherited and de novo 22q11.2 distal duplications in two patients with autistic features, speech delay and no dysmorphology.

In a screen of patients by fluorescence in-situ hybridization and array comparative genomic hybridization in the past two years (July 2007--July 2009), we identified two patients with duplications in the 22q11.22-23, occurring outside the common DiGeorge syndrome/valocardiofacial syndrome region. Fluorescent in-situ hybridization, multiplex ligation-dependent probe amplification and high density bacterial artificial chromosomes and oligo arrays were used to identify the extent of the duplications. In one patient the duplication extended from LCR22-E/5 to LCR22-H/8, which is similar to recently described 22q11.2 distal duplications, while in the second patient, a de novo duplication was identified extending between LCR22-E/5 to LCR22-F/6. The second proband also harbored a de novo 15q14 duplication, complicating phenotype interpretation. The patients were affected with speech delay and autistic features, but neither reported cardiac concern or dysmorphic features.