Continuing role for classical cytogenetics: Case report of a boy with ring syndrome caused by complete ring chromosome 4 and review of literature.

Constitutional ring chromosomes can be found for all human chromosomes and are very rare chromosomal abnormalities. A complete ring chromosome without loss of genetic material results from fusion of subtelomeric regions or telomere-telomere fusion. In cases of complete ring chromosome, an increased incidence of severe growth failure with no or only minor anomalies has been observed and attributed to ring syndrome. Ring syndrome is thought to be caused by "dynamic mosaicism" due to ring instability. We report a 6-year-old boy with de novo ring chromosome 4 and typical characteristics of the ring syndrome, namely, proportionate severe growth failure, microcephaly, and minor anomalies. Cytogenetic studies showed complete ring chromosome 4 with mitotic instability. Microarray gave normal results, thus excluding the loss of detectable genetic material. The literature of complete ring chromosome 4 is reviewed. Our case report supports the theory of ring syndrome. No studies about the effects and possible side effects of growth hormone therapy on patients with ring chromosomes have yet been published. We suggest that cytogenetic monitoring of the rate of secondary aberrations in patients with ring chromosome undergoing growth hormone therapy might be feasible. Since the diagnosis would have been missed by molecular karyotyping, our case report underlines the continuing role of classical cytogenetics for the evaluation of structural chromosomal abnormalities in patients with mental and/or physical anomalies. Standard karyotyping is still indispensable and should have an ongoing role as first-tier analysis together with molecular karyotyping. © 2017 Wiley Periodicals, Inc.

Menkes disease with discordant phenotype in female monozygotic twins.

Menkes disease (MD) is a rare X-linked recessive disorder caused by mutations in the ATP7A gene. This neurodegenerative disorder typically affects males and is characterized by impaired copper distribution and the malfunction of several copper-dependent enzymes. We report clinically discordant female monozygotic twins (MZT) with a heterozygous ATP7A mutation. One twin girl is healthy at the current age of 4 years, whereas the other twin girl developed classical MD, showed disease stabilization under copper histidine treatment but died at the age of 3 years. Presumably, the affected girl developed MD due to skewed X inactivation, although this could not be demonstrated in two tissues (blood, buccal mucosa). This case is a rare example of an affected girl with MD and shows the possibility of a discordant phenotype in MZT girls. As speculated in other X-linked diseases, the process of monozygotic twinning may be associated with skewed X inactivation leading to a discordant phenotype.

Clinical and molecular characterization of the BRCA2 p.Asn3124Ile variant reveals substantial evidence for pathogenic significance.

Variants of uncertain clinical significance (VUS) in the high-penetrance breast cancer susceptibility genes BRCA1 and BRCA2 represent a major obstacle in genetic counseling of high-risk breast cancer families. We analyzed a missense VUS located in BRCA2 (p.Asn3124Ile; HGVS: BRCA2 c.9371A > T) present in seven independent high-risk breast cancer families that were counseled and genetically tested in South-West Germany. The VUS was identified by DNA sequencing. We analyzed co-occurrence with deleterious BRCA1/2 mutations, segregation, evolutionary conservation, in silico impact prediction, and prevalence in the general population. All carriers of the VUS suffered from breast or ovarian cancer. In two families, an additional high burden of other cancers such as pancreatic, prostate, and gastric cancers was reported, one further family included two cases of male breast cancer. The VUS did not co-occur with deleterious BRCA1/2 mutations and segregated in two affected individuals of one family. In contrast to the 7/1,347 (0,5 %) tested high-risk BC families without clearly pathogenic mutations in BRCA1/2, none of 3,126 healthy population controls sharing the same ethnic and geographical background were found to carry this VUS (p = 0.0002). In-silico prediction revealed strong evolutionary conservation of the asparagine residue, residing in the C-terminal oligonucleotide-binding-fold-3 region, and a most likely damaging impact of this exchange on the protein structure. The BRCA2 p.Asn3124Ile (BRCA2 c.9371A > T) variant is a rare mutation with a damaging effect on the BRCA2 protein that is strongly associated with familial breast and ovarian cancer risk, indicating its most likely pathogenic nature and clinical relevance.

Molecular and clinical characterization of an in frame deletion of uncertain clinical significance in the BRCA2 gene.

In this study, we analyzed a "variant of uncertain significance" (VUS) located in exon 23 of the BRCA2 gene exhibited by six members of five distinct families with hereditary breast cancer (BC). The variant was identified by DNA sequencing, and cDNA analysis revealed its co-expression with wild-type mRNA. We analyzed co-occurrence with other pathological mutations in BRCA1/2, performed a case-control study, looked for evolutionary data and used in-silico analyses to predict its potential clinical significance. Sequencing revealed an in frame deletion of 126 nucleotides in exon 23, leading to a deletion of 42 amino acids (c.9203_9328del126, p.Pro2992_Thr3033del). All of the VUS-carriers suffered from either BC or ovarian/pancreatic cancer. No other definite pathologic mutation of BRCA genes was found in the five families. The identified deletion could not be observed in a control cohort of 2,652 healthy individuals, but in 5 out of 916 (0.5%) tested BC families without a bona fide pathogenic BRCA1/2 mutation (P = 0.0011). According to these results, the in frame deletion c.9203_9328del126 is a rare mutation strongly associated with familial BC. In summary, our investigations indicate that this BRCA2 deletion is pathogenic.