Coexisting Conditions Modifying Phenotypes of Patients with 22q11.2 Deletion Syndrome.

22q11.2 deletion syndrome (22q11.2DS) is the most common genomic disorder with an extremely broad phenotypic spectrum. The aim of our study was to investigate how often the additional variants in the genome can affect clinical variation among patients with the recurrent deletion. To examine the presence of additional variants affecting the phenotype, we performed microarray in 82 prenatal and 77 postnatal cases and performed exome sequencing in 86 postnatal patients with 22q11.2DS. Within those 159 patients where array was performed, 5 pathogenic and 5 likely pathogenic CNVs were identified outside of the 22q11.2 region. This indicates that in 6.3% cases, additional CNVs most likely contribute to the clinical presentation. Additionally, exome sequencing in 86 patients revealed 3 pathogenic (3.49%) and 5 likely pathogenic (5.81%) SNVs and small CNV. These results show that the extension of diagnostics with genome-wide methods can reveal other clinically relevant changes in patients with 22q11 deletion syndrome.

Comparative Genomic Hybridization to Microarrays in Fetuses with High-Risk Prenatal Indications: Polish Experience with 7400 Pregnancies.

The aim of this study was to determine the suitability of the comparative genomic hybridization to microarray (aCGH) technique for prenatal diagnosis, but also to assess the frequency of chromosomal aberrations that may lead to fetal malformations but are not included in the diagnostic report. We present the results of the aCGH in a cohort of 7400 prenatal cases, indicated for invasive testing due to ultrasound abnormalities, high-risk for serum screening, thickened nuchal translucency, family history of genetic abnormalities or congenital abnormalities, and advanced maternal age (AMA). The overall chromosomal aberration detection rate was 27.2% (2010/7400), including 71.2% (1431/2010) of numerical aberrations and 28.8% (579/2010) of structural aberrations. Additionally, the detection rate of clinically significant copy number variants (CNVs) was 6.8% (505/7400) and 0.7% (57/7400) for variants of unknown clinical significance. The detection rate of clinically significant submicroscopic CNVs was 7.9% (334/4204) for fetuses with structural anomalies, 5.4% (18/336) in AMA, 3.1% (22/713) in the group of abnormal serum screening and 6.1% (131/2147) in other indications. Using the aCGH method, it was possible to assess the frequency of pathogenic chromosomal aberrations, of likely pathogenic and of uncertain clinical significance, in the groups of cases with different indications for an invasive test.

Diverse clinical outcome of Hunter syndrome in patients with chromosomal aberration encompassing entire and partial IDS deletions: what is important for early diagnosis and counseling?

Our study aims to delineate the syndromology of Hunter syndrome (MPSII), by presenting three patients with different clinical courses, caused by different genetic mechanisms. Single-nucleotide variants (SNV) or small deletions encompassing the iduronate-2-sulfatase (IDS) gene are identified in the majority of affected individuals, while deletion of contiguous genes or whole IDS gene (described herein) has been reported rarely, mainly in patients with a severe Hunter syndrome presentation. There is; however, lack of reliable genotype-phenotype correlation, especially regarding anthropometric parameters, and thus our understanding of MPSII pathophysiology is not complete. On the basis of our observations, we would like to draw attention to the fact that neurological manifestations observed in patients with contiguous gene deletions, encompassing the IDS gene, may significantly differ from those observed in SNV. The phenotype is; however, difficult to predict and depends on the type (deletion/duplication), size (small/large) of aberration, and gene content. Moreover, it also has implications for genetic counseling, and recurrence risk in those families differs from the usual situation and must be clarified by parental chromosomal studies.

Multiple Small Supernumerary Marker Chromosomes Resulting from Maternal Meiosis I or II Errors.

We present 2 cases with multiple de novo supernumerary marker chromosomes (sSMCs), each derived from a different chromosome. In a prenatal case, we found mosaicism for an sSMC(4), sSMC(6), sSMC(9), sSMC(14) and sSMC(22), while a postnatal case had an sSMC(4), sSMC(8) and an sSMC(11). SNP-marker segregation indicated that the sSMC(4) resulted from a maternal meiosis II error in the prenatal case. Segregation of short tandem repeat markers on the sSMC(8) was consistent with a maternal meiosis I error in the postnatal case. In the latter, a boy with developmental/psychomotor delay, autism, hyperactivity, speech delay, and hypotonia, the sSMC(8) was present at the highest frequency in blood. By comparison to other patients with a corresponding duplication, a minimal region of overlap for the phenotype was identified, with CHRNB3 and CHRNA6 as dosage-sensitive candidate genes. These genes encode subunits of nicotinic acetylcholine receptors (nAChRs). We propose that overproduction of these subunits leads to perturbed component stoichiometries with dominant negative effects on the function of nAChRs, as was shown by others in vitro. With the limitation that in each case only one sSMC could be studied, our findings demonstrate that different meiotic errors lead to multiple sSMCs. We relate our findings to age-related aneuploidy in female meiosis and propose that predivision sister-chromatid separation during meiosis I or II, or both, may generate multiple sSMCs.

Application of array comparative genomic hybridization in 256 patients with developmental delay or intellectual disability.

We used whole-genome exon-targeted oligonucleotide array comparative genomic hybridization (array CGH) in a cohort of 256 patients with developmental delay (DD)/intellectual disability (ID) with or without dysmorphic features, additional neurodevelopmental abnormalities, and/or congenital malformations. In 69 patients, we identified 84 non-polymorphic copy-number variants, among which 41 are known to be clinically relevant, including two recently described deletions, 4q21.21q21.22 and 17q24.2. Chromosomal microarray analysis revealed also 15 potentially pathogenic changes, including three rare deletions, 5q35.3, 10q21.3, and 13q12.11. Additionally, we found 28 copy-number variants of unknown clinical significance. Our results further support the notion that copy-number variants significantly contribute to the genetic etiology of DD/ID and emphasize the efficacy of the detection of novel candidate genes for neurodevelopmental disorders by whole-genome array CGH.

Application of array comparative genomic hybridization in 102 patients with epilepsy and additional neurodevelopmental disorders.

Copy-number variants (CNVs) collectively represent an important cause of neurodevelopmental disorders such as developmental delay (DD)/intellectual disability (ID), autism, and epilepsy. In contrast to DD/ID, for which the application of microarray techniques enables detection of pathogenic CNVs in -10-20% of patients, there are only few studies of the role of CNVs in epilepsy and genetic etiology in the vast majority of cases remains unknown. We have applied whole-genome exon-targeted oligonucleotide array comparative genomic hybridization (array CGH) to a cohort of 102 patients with various types of epilepsy with or without additional neurodevelopmental abnormalities. Chromosomal microarray analysis revealed 24 non-polymorphic CNVs in 23 patients, among which 10 CNVs are known to be clinically relevant. Two rare deletions in 2q24.1q24.3, including KCNJ3 and 9q21.13 are novel pathogenic genetic loci and 12 CNVs are of unknown clinical significance. Our results further support the notion that rare CNVs can cause different types of epilepsy, emphasize the efficiency of detecting novel candidate genes by whole-genome array CGH, and suggest that the clinical application of array CGH should be extended to patients with unexplained epilepsies.

[Clinical manifestation of chromosome 2 long arm terminal deletion--presentation of four cases]. / Obraz fenotypowy delecji terminalnej dlugiego ramienia chromosomu 2 pary--prezentacja czterech przypadków.

Terminal deletion of the long arm of chromosome 2 belongs to the most common structural aberrations of subtelomeric chromosomal regions. Clinical manifestations of this syndrome comprise: global psychomotor delay, moderate to severe mental retardation with specific facial dysmorphism. In some cases a phenotype similar to Albright's hereditary osteodystrophy (AHO) may also be observed (short stature, obesity, brachydactyly). The paper covers the characteristics of clinical features in four cases of terminal deletions in 2q36.2, 2q37.1 and 2q37.3 identified in routine cytogenetic study and fluorescent in situ hybridization (FISH) technique. In one case the deletion of subtelomeric region of chromosome 2 (2q37.3) occurred as a result of reciprocal translocation between chromosomes 2 and 7. A comparison was made of clinical symptoms present in our patients with relevant data concerning other cases of 2q monosomy, described in specialized publications.