Uniparental disomy 7 in Silver--Russell syndrome and primordial growth retardation

Maternal uniparental disomy for the entire chromosome 7 hasso far been reported in three patients with intrauterine andpostnatal growth retardation. Two were detected because theywere homozygous for a cystic fibrosis mutation for which onlythe mother was heterozygous, and one because he was homozygousfor a rare COL1A2 mutation. We investigated 35 patients witheither the Silver-Russell syndrome or primordial growth retardationand their parents with PCR markers to search for uniparentaldisomy 7. Four of 35 patients were found to have maternal disomy,including three with isodisomy and one with heterodisomy. Thedata confirm the hypothetical localization of a maternally imprintedgene (or more than one such gene) on chromosome 7. It is suggestedto search for UPD 7 in families with an offspring with sporadicSilver-Russell syndrome or primordial growth retardation.     

Molecular and cytogenetic characterization of a non-mosaic isodicentric Y chromosome in a patient with Klinefelter syndrome

We report on an adult male with Klinefelter phenotype and an isodicentric Y chromosome (47,XX,+idic(Y)(q12)), a combination which has to the best of our knowledge not been reported before. The patient was hospitalized in forensic psychiatry because of repeated delinquency, aggressive, aberrant and inappropriate behavior, and borderline intelligence. Molecular cytogenetic studies (FISH) showed that the SRY gene was present on both ends of the idicY, while there was only one signal for the Yq subtelomere probe. Molecular investigations by multiplex PCR, using STS markers covering the short and long arm of the Y chromosome did not indicate a deletion of Y chromosomal material. Molecular investigations of STR markers located on Xp22.3 and Xq28 indicated paternal origin of the additional X chromosome and an error in paternal meiosis I. Results of FISH analysis and molecular investigations are compatible with a phenotype as described for individuals with a 48,XXYY karyotype and support the findings that isodicentric Y chromosomes are frequently accompanied by other sex chromosomal abnormalities.     

Comparative analysis of isodisomic and heterodisomic segments in cases with maternal uniparental disomy 14 suggests more than one imprinted region

The results of molecular investigations of 21 cases with complete or segmental maternal uniparental disomy (UPD) 14 published in the literature were compared with respect to isodisomic and heterodisomic segments. The aim of the study was to find hints toward imprinted regions other than the recently defined imprinted segment 14q32. Three regions with no isodisomic molecular marker were found. The most distal of these regions located on 14q32.12 and 14q32.13 supports the hypothesis of genomic imprinting as the cause of the maternal UPD 14 phenotype by synteny to the maternally imprinted region on mouse distal chromosome 12 and correlation with the recently defined imprinting cluster on human chromosome 14q32. The other two heterodisomic areas located on 14q11.2-->14q12 and 14q21.1-->14q31.2 are hints toward one or more additional regions of genomic imprinting on human chromosome 14.     

Disruption of EXOC6B in a patient with developmental delay,epilepsy, and a de novo balanced t(2;8) translocation

Most balanced chromosomal aberrations are not associated with a clinical phenotype, however, in some patients they may disrupt gene structure. With the development of various next-generation sequencing techniques, fast and specific analyses of the breakpoint regions of chromosomal rearrangements are possible. Here, we report on a 19-year-old woman with a de novo balanced translocation t(2;8)(p13.2;q22.1) and a severe clinical phenotype including intellectual disability, epilepsy, behavioral features resembling autism, and minor dysmorphic features. By next-generation sequencing, we defined the breakpoints and found disruption of the exocyst complex component 6B (EXOC6B) gene in intron 1 on chromosome 2p13.2 involving two Alu elements with a homology of 81%. No gene was found at the respective breakpoint on chromosome 8. Expression analysis of the EXOC6B in blood lymphocytes and buccal smear revealed reduced expression in the patient in comparison with the control. Our findings in combination with one recently published case and one other patient listed in DECIPHER v5.1 indicate EXOC6B as a gene relevant for intellectual development and electrophysiological stability.     

Don’t miss patients with atypical FMR1 mutations: dysmorphism and clinical features in a boy with a partially methylated FMR1 full mutation

Fragile X syndrome characterized by intellectual disability (ID), facial dysmorphism, and postpubertal macroorchidism is the most common monogenic cause of ID. It is typically induced by an expansion of a CGG repeat in the fragile X mental retardation 1 (FMR1) gene on Xq27 to more than 200 repeats. Only rarely patients have atypical mutations in the FMR1 gene such as point mutations, deletions, or unmethylated/partially methylated full mutations. Most of these patients show a minor phenotype or even appear clinically healthy. Here, we report the dysmorphism and clinical features of a 17-year-old boy with a partially methylated full mutation of approximately 250 repeats. Diagnosis was made subsequently to the evaluation of a FMR1 premutation as the cause for maternal premature ovarian failure. Dysmorphic evaluation revealed no strikingly long face, no prominent forehead/frontal bossing, no prominent mandible, no macroorchidism, and a head circumference in the lower normal range. Acquisition of a driving license for mopeds and unaccompanied rides by public transport in his home province indicate rather mild ID (IQ?=?58). Conclusion: This adolescent demonstrates that apart from only minor ID, patients with a partially methylated FMR1 full mutation present less to absent pathognomonic facial dysmorphism, thus emphasizing the impact of family history for a straightforward clinical diagnosis.     

Molecular breakpoint analysis and relevance of variable mosaicism in a woman with short stature,primary amenorrhea,unilateral gonadoblastoma,and a 46,X,del(Y)(q11)/45,X karyotype

An impressive LOD score of 6.5 has recently been reported for schizophrenia on chromosome 1q21-22 in large families from eastern Canada [Brzustowicz et al., 2000: Science 288:678-682]. We did not reproduce such a finding in large pedigrees of eastern Québec based on seven markers spanning the 1p13-1q22 region and using both the models and phenotypes of Brzustowicz et al. and those used in our ongoing genome scan in 21 large French Canadian families. There was no significant total LOD scores in that chromosomal region (a maximum of 0.57) either for schizophrenia or bipolar disorders, nor any signal in individual large pedigrees. However, the samples of Brzustowicz et al. and ours differed in terms of their origins, the latter being of French ancestry and the former of Celtic and German descent. Population difference, genetic heterogeneity, and differences in ascertainment might explain the lack of replication. The result reported by Brzustowicz et al. cannot be discarded and should probably be considered as a susceptibility locus for a subset of the schizophrenic population.     

Prenatal testing for uniparental disomy: indications and clinical relevance.

This review aims to provide a rational and ethical basis for prenatal testing for uniparental disomy (UPD) in cases with abnormal ultrasound findings or numeric and/or structural chromosomal aberrations in chorionic villous or amniotic fluid samples. The clinical phenotypes of the genomic imprinting-associated paternal UPD 6 (transient neonatal diabetes mellitus), maternal UPD 7 (Silver-Russell syndrome), paternal UPD 11p (Beckwith-Wiedemann syndrome), maternal UPD 14 (precocious puberty, short stature and highly variable developmental delay), paternal UPD 14 (polyhydramnios and a bell-shaped thorax), maternal UPD 15 (Prader-Willi syndrome), paternal UPD 15 (Angelman syndrome), maternal UPD 16 and UPD 20, as well as the diagnostic options, are summarized. In addition, the clinical impact of UPD testing and its relevance in various prenatal diagnostic situations are discussed. As a general rule, prenatal UPD testing, following genetic counseling, is justified if paternal UPD 14, maternal UPD 15 or paternal UPD 15 are suspected. In contrast, considering the mild phenotypes of paternal UPD 6 and maternal UPD 7, prenatal UPD testing is questionable. Because of the highly variable phenotype for paternal UPD 11p, maternal UPD 14 and maternal UPD 16, prenatal testing should be discussed critically on an individual basis. For all other chromosomes, prenatal UPD testing is purely academic and should therefore not be performed on a routine basis, particularly because a positive result might confuse the parents more than it actually helps them.     

Parental origin of apparently balanced de novo complex chromosomal rearrangements investigated by microdissection,whole genome amplification,and microsatellite‐mediated haplotype analysis

Grossmann V, Höckner M, Karmous‐Benailly H, Liang D, Puttinger R, Quadrelli R, Röthlisberger B, Huber A, Wu L, Spreiz A, Fauth C, Erdel M, Zschocke J, Utermann G, Kotzot D. Parental origin of apparently balanced de novo complex chromosomal rearrangements investigated by microdissection, whole genome amplification, and microsatellite‐mediated haplotype analysis. Complex chromosomal rearrangements (CCRs) are rare findings in clinical cytogenetics. As a result of the high risk of unbalanced segregation, familial cases are even rarer and maternal transmission occurs more frequently than paternal transmission. Analogous to Drosophila and mice, as well as to CCRs involving the Y chromosome or a clinically relevant associated deletion, a preferential origin in spermatogenesis has been assumed but not proven directly and systematically thus far. Here, we investigated three healthy adults, one healthy child, and one child with multiple congenital anomalies and various balanced de novo CCRs. The analyses were performed in each case on 10 copies of a derivative chromosome and their normal homologs by glass‐needle microdissection, whole genome amplification (WGA), and microsatellite‐mediated haplotype analysis. With respect to the number of chromosomes involved in each case and in all cases together, the number of chromosomal segments in each case and in all cases together, and the number of breakpoints in each case and in all cases together, the conformity for paternal origin of all derivative chromosomes and maternal origin of their normal homologs makes formation in paternal germline more likely than a postzygotic formation with an accidental uniformity. In conclusion, our results confirm the preferential formation of de novo balanced CCRs in the paternal germline.