Non-disjunction of chromosome 13

We performed a molecular study with 21 microsatellites on a sample of 82 trisomy 13 conceptuses, the largest number of cases studied to date. The parental origin was determined in every case and in 89% the extra chromosome 13 was of maternal origin with an almost equal number of maternal MI and MII errors. The latter finding is unique among human autosomal trisomies, where maternal MI (trisomies 15, 16, 21, 22) or MII (trisomy 18) errors dominate. Of the nine paternally derived cases five were of MII origin but none arose from MI errors. There was some evidence for elevated maternal age in cases with maternal meiotic origin for liveborn infants. Maternal and paternal ages were elevated in cases with paternal meiotic origin. This is in contrast to results from a similar study of non-disjunction of trisomy 21 where paternal but not maternal age was elevated. We find clear evidence for reduced recombination in both maternal MI and MII errors and the former is associated with a significant number of tetrads (33%) that are nullichiasmate, which do not appear to be a feature of normal chromosome 13 meiosis. This study supports the evidence for subtle chromosome-specific influences on the mechanisms that determine non-disjunction of human chromosomes, consistent with the diversity of findings for other trisomie

Subtelomeric study of 132 patients with mental retardation reveals 9 chromosomal anomalies and contributes to the delineation of submicroscopic deletions of 1pter, 2qter, 4pter, 5qter and 9qter

BACKGROUND: Cryptic chromosome imbalances are increasingly acknowledged as a cause for mental retardation and learning disability. New phenotypes associated with specific rearrangements are also being recognized. Techniques for screening for subtelomeric rearrangements are commercially available, allowing the implementation in a diagnostic service laboratory. We report the diagnostic yield in a series of 132 subjects with mental retardation, and the associated clinical phenotypes. METHODS: We applied commercially available subtelomeric fluorescence in situ hybridization (FISH). All patients referred for subtelomeric screening in a 5-year period were reviewed and abnormal cases were further characterized clinically and if possible molecularly. RESULTS: We identified nine chromosomal rearrangements (two of which were in sisters) corresponding to a diagnostic yield of approx. 7%. All had dysmorphic features. Five had imbalances leading to recognizable phenotypes. CONCLUSION: Subtelomeric screening is a useful adjunct to conventional cytogenetic analyses, and should be considered in mentally retarded subjects with dysmorphic features and unknown cause

No evidence for pathogenic variants or maternal effect of ZFP57 as the cause of Beckwith-Wiedemann Syndrome

Beckwith–Wiedemann syndrome (BWS) is an overgrowth syndrome, which, in 50–60% of sporadic cases, is caused by hypomethylation of KCNQ1OT1 differentially methylated region (DMR) at chromosome 11p15.5. The underlying defect of this hypomethylation is largely unknown. Recently, recessive mutations of the ZFP57 gene were reported in patients with transient neonatal diabetes mellitus type 1, showing hypomethylation at multiple imprinted loci, including KCNQ1OT1 DMR in some. The aim of our study was to determine whether ZFP57 alterations were a genetic cause of the hypomethylation at KCNQ1OT1 DMR in patients with BWS. We sequenced ZFP57 in 27 BWS probands and in 23 available mothers to test for a maternal effect. We identified three novel, presumably benign sequence variants in ZFP57; thus, we found no evidence for ZFP57 alterations as a major cause in sporadic BWS cases

Genome-wide DNA methylation analysis of transient neonatal diabetes type 1 patients with mutations in ZFP57

AbstractBackground: Transient neonatal diabetes mellitus 1 (TNDM1) is a rare imprinting disorder characterized byintrautering growth retardation and diabetes mellitus usually presenting within the first six weeks of life andresolves by the age of 18 months. However, patients have an increased risk of developing diabetes mellitus type 2later in life. Transient neonatal diabetes mellitus 1 is caused by overexpression of the maternally imprinted genesPLAGL1 and HYMAI on chromosome 6q24. One of the mechanisms leading to overexpression of the locus ishypomethylation of the maternal allele of PLAGL1 and HYMAI. A subset of patients with maternal hypomethylationat PLAGL1 have hypomethylation at additional imprinted loci throughout the genome, including GRB10, ZIM2(PEG3), MEST (PEG1), KCNQ1OT1 and NESPAS (GNAS-AS1). About half of the TNDM1 patients carry mutations in ZFP57,a transcription factor involved in establishment and maintenance of methylation of imprinted loci. Our objectivewas to investigate whether additional regions are aberrantly methylated in ZFP57 mutation carriers.Methods: Genome-wide DNA methylation analysis was performed on four individuals with homozygous orcompound heterozygous ZFP57 mutations, three relatives with heterozygous ZFP57 mutations and five controls.Methylation status of selected regions showing aberrant methylation in the patients was verified usingbisulfite-sequencing.Results: We found large variability among the patients concerning the number and identity of the differentiallymethylated regions, but more than 60 regions were aberrantly methylated in two or more patients and a novelregion within PPP1R13L was found to be hypomethylated in all the patients. The hypomethylated regions incommon between the patients are enriched for the ZFP57 DNA binding motif.Conclusions: We have expanded the epimutational spectrum of TNDM1 associated with ZFP57 mutations andfound one novel region within PPP1R13L which is hypomethylated in all TNDM1 patients included in this study.Functional studies of the locus might provide further insight into the etiology of the disease

Deletions and rearrangements of the H19/IGF2 enhancer region in patients with Silver-Russell syndrome and growth retardation

Silver–Russell syndrome (SRS) is characterised by prenatal and postnatal growth retardation, dysmorphic facial features, and body asymmetry. In 35–60% of SRS cases the paternally methylated imprinting control region (ICR) upstream of the H19 gene (H19-ICR) is hypomethylated, leading to downregulation of IGF2 and bi-allelic expression of H19. H19 and IGF2 are reciprocally imprinted genes on chromosome 11p15. The expression is regulated by the imprinted methylation of the ICR, which modulates the transcription of H19 and IGF2 facilitated by enhancers downstream of H19. A promoter element of IGF2, IGF2P0, is differentially methylated equivalently to the H19-ICR, though in a small number of SRS cases this association is disrupted—that is, hypomethylation affects either H19-ICR or IGF2P0. Three pedigrees associated with hypomethylation of IGF2P0 in the probands are presented here, two with paternally derived deletions, and one with a balanced translocation of inferred paternal origin. They all have a breakpoint within the H19/IGF2 enhancer region. One proband has severe growth retardation, the others have SRS. This is the first report of paternally derived structural chromosomal mutations in 11p15 causing SRS. These cases define a novel aetiology of the growth retardation in SRS, namely, dissociation of IGF2 from its enhancers. <br/