Dieter Kotzot

Heterozygous mutations in ANKH , the human ortholog of the mouse progressive ankylosis gene, result in craniometaphyseal dysplasia

Heterozygous mutations in ANKH , the human ortholog of the mouse progressive ankylosis gene, result in craniometaphyseal dysplasia

Abnormal phenotypes in uniparental disomy (UPD) : Fundamental aspects and a critical review with bibliography of UPD other than 15

Uniparental disomy (UPD) is the inheritance of both homologous chromosomes from only one parent. The bases are always two events, either two meiotic, or one meiotic and one mitotic, or two mitotic. An aberrant imprint, homozygosity of autosomal recessive gene mutations, homozygosity of X-chromosomal disorders in females, and father-to-son transmission of X-linked traits are the possible and yet repeatedly documented consequences sometimes associated with unfavorable handicaps. Fertilization of a disomic (=hyperhaploid) gamete by a gamete monosomic for the same chromosome and subsequent loss of the normally inherited chromosome (trisomy rescue) is the most frequently supposed mechanism of formation and might result in mosaicism in the placenta or even in a subset of fetal tissues. This low-level mosaicism can remain undetected and renders the delineation of a phenotype more difficult. Therefore, the phenotype of cases with UPD is determined by mosaicism, genomic imprinting, the nonmendelian inheritance of monogenic disorders, or by a combination of all these factors. A survey of all reported cases demonstrates a preponderance of maternal versus paternal UPD (approximately 3:1) and an unequal chromosomal distribution. Most likely, deleterious trisomy mosaicism, imprinted genes, the nature of the chromosome itself, the clinical interest in a single chromosome, and, last but not least, an ascertainment bias are therefore responsible.

Uniparental disomy (UPD) other than 15 : Phenotypes and bibliography updated

Uniparental disomy (UPD) describes the inheritance of a pair of chromosomes from only one parent. The concept was introduced in Medical Genetics by Engel (1980); Am J Med Genet 6:137–143. Aside UPD 15, which is the most frequent one, up to now (February 2005) 197 cases with whole chromosome maternal UPD other than 15 (124 X heterodisomy, 59 X isodisomy, and 14 cases without information of the mode of UPD) and 68 cases with whole chromosome paternal UPD other than 15 (13 X heterdisomy, 53 X isodisomy, and 2 cases without information of the mode of UPD) have been reported. In this review we discuss briefly the problems associated with UPD and provide a comprehensive clinical summary with a bibliography for each UPD other than 15 as a guide for genetic counseling.

Complex and segmental uniparental disomy updated

Objective: To review all cases with segmental and/or complex uniparental disomy (UPD) and to discuss the impact of these cases on medical genetics. Design: Searching for published reports in PubMed and in the abstract books of the annual meetings of the American Society of Human Genetics and the European Society of Human Genetics up to March 2008. Results: In total, 26 cases with segmental UPD and a normal karyotype, 38 cases with UPD of a whole chromosome and a simple reciprocal or non-homologous Robertsonian translocation, four cases each with two isochromosomes and UPD of the short arm isochromosome and opposite UPD of the long arm isochromosome, three cases with UPD and an isochromosome of the short arm and the long arm of a metacentric or a submetacentric chromosome, one case with maternal UPD and an isochromosome 8 associated with a homozygous deletion (8)(p23.3pter), 42 cases with UPD and an isochromosome of the long arm of an acrocentric chromosome, 33 cases with UPD and a supernumerary marker or ring chromosome, 17 cases with UPD of a whole or parts of a chromosome and a complex karyotype, 13 cases with most likely mosaicism for genome wide paternal UPD, and three cases with most likely mosaicism for genome wide maternal UPD were found. Conclusion: This update shows that, in particular, the number of reported cases with segmental UPD or UPD associated with a marker chromosome clearly increased within the last few years, and that the investigation of both parents in cases with homozygosity of an autosomal recessively inherited mutation in some cases might help improve genetic counselling, resulting in a reduced recurrence risk in the case of UPD. Moreover, cases with segmental or complex UPD show that meiosis and early postzygotic mitoses seem to be more complex events than previously thought. For the formation of all kinds of segmental or complex UPD or genome wide UPD mosaicism, always a fortunate co-occurrence of meiotic or mitotic recombination, abnormal segregation, and subsequent correction are necessary. No case of recurrence has been reported until now. Therefore, in subsequent pregnancies invasive prenatal diagnosis is not necessarily indicated.

Maternal uniparental disomy 7 - review and further delineation of the phenotype.

Abstract Uniparental disomy (UPD) is defined as the inheritance of both homologous chromosomes from only one parent. So far, maternal UPD 7 has been described in 28 cases. Here, we report 4 new cases, present clinical information of 5 cases previously reported by us, and review the clinical and molecular findings of all 32 cases. We found a phenotype characterized by pre- and postnatal growth retardation, occipitofrontal head circumference in the lower normal range, a triangular face, and retarded bone maturation. Findings of the facial gestalt included a high and broad forehead and a pointed chin. A broad mouth with down-turned corners, prominent ears, café-au-lait spots, hemihypotrophy, or clinodactyly were rarely present. Psychomotor development was delayed in 6 cases. The clinical findings strikingly resemble the phenotype of the heterogeneous Silver-Russell syndrome (SRS). Other anomalies were less frequently found than in SRS. Molecular investigations revealed 11 cases with isodisomy and 17 cases with heterodisomy. In 4 cases this information was not available. From the allelic distribution of the microsatellites investigated, 9 cases might be the consequence of an error at maternal meiosis I, and 6 cases might be due to non-disjunction at maternal meiosis II. Three of the 17 heterodisomic cases had trisomy 7 in chorionic villi, in the remaining cases no prenatal diagnosis through chorionic villus sampling was reported. Conclusion Maternal UPD 7 should be investigated in children with pre- and postnatal growth retardation and a facial gestalt characterized by a high and broad forehead and a pointed chin, as well as in confined placental mosaicism for trisomy 7.

Maternal uniparental disomy 7 and Silver-Russell syndrome - clinical update and comparison with other subgroups.

Maternal uniparental disomy (UPD) 7 is found in approximately 5% of patients with Silver-Russell syndrome. By a descriptive and comparative clinical analysis of all published cases (more than 60 to date) their phenotype is updated and compared with the clinical findings in patients with Sliver-Russell syndrome (SRS) of either unexplained etiology or epimutations of the imprinting center region 1 (ICR1) on 11p15. The higher frequency of relative macrocephaly and high forehead/frontal bossing makes the face of patients with epimutations of the ICR1 on 11p15 more distinctive than the face of cases with SRS of unexplained etiology or maternal UPD 7. Because of the distinct micrognathia in the latter, their triangular facial gestalt is more pronounced than in the other groups. However, solely by clinical findings patients with maternal UPD 7 cannot be discriminated unambiguously from patients with epimutations of the ICR1 on 11p15 or SRS of unexplained etiology. Therefore, both loss of methylation of the ICR1 on 11p15 and maternal UPD 7 should be investigated for if SRS is suspected.

Etiology of chest wall deformities—a genetic review for the treating physician

Chest wall deformities such as pectus excavatum, pectus carinatum, and cleft sternum can be isolated malformations or dysmorphic features of genetic associations, monogenic disorders, and various numeric and structural chromosomal aberrations. In contrast to the most important syndromes such as Marfan syndrome or Noonan syndrome that can be associated with a chest wall deformity and for which the causative genes are known, etiology of isolated chest wall deformities is still a matter of research. Therefore, an interdisciplinary approach, particularly in patients with additional symptoms is strongly recommended to choose the best therapeutic approach for each patient and its family.

Parental origin and mechanisms of formation of cytogenetically recognisable de novo direct and inverted duplications

Cytogenetic, FISH, and molecular results of 20 cases with de novo tandem duplications of 18 different autosomal chromosome segments are reported. There were 12 cases with direct duplications, three cases with inverted duplications, and five in whom determination of direction was not possible. In seven cases a rearrangement between non-sister chromatids (N-SCR) was found, whereas in the remaining 13 cases sister chromatids (SCR) were involved. Paternal and maternal origin (7:7) was found almost equally in cases with SCR (3:4) and N-SCR (4:3). In the cases with proven inversion, there was maternal and paternal origin in one case each. Twenty three out of 43 cytogenetically determined breakpoints correlated with common or rare fragile sites. In five cases, including all those with proven inverse orientation, all breakpoints corresponded to common or rare fragile sites. In at least two cases, one with an interstitial duplication (dup(19)(q11q13)) and one with a terminal duplication (dup(8) (p10p23)), concomitant deletions (del(8) (p23p23.3) and del(19)(q13q13)) were found.

Phenotype of the Williams-Beuren syndrome associated with hemizygosity at the elastin locus

To correlate presence or absence of a 7q11 microdeletion with the clinical picture of the Williams-Beuren syndrome (WBS), we investigated 29 patients with a clinical diagnosis of WBS or WBS-like features, aged 1–30 years, using molecular analysis and/or fluorescent in situ hybridization (FISH). Deletions at 7q11 were found in 75% of the patients (22 out of 29). Nine deletions occurred on a paternal, and ten on a maternal chromosome; three deletions were demonstrated by FISH only, and parental origin could thus not be determined. All deletion patients aged between 2 years and puberty displayed a distinct pattern of facial features (including periorbital fullness, short nose with flat bridge, wide mouth, and full lips and cheeks), the characteristic outgoing social behaviour, as well as moderate growth and mental retardation. Twothirds (15 out of 22) had a cardiovascular malformation, but only one third (7 of 22) had supravalvular aortic stenosis (SVAS). A stellate iris pattern was also present in one-third of the patients only. In the four adult patients with 7q11 deletions, there was prominence of the lower lip whereas fullness of cheeks and periorbital tissue was not seen.ConclusionThis study confirms that WBS has a unique clinical picture which can be diagnosed clinically, but also shows that the relative frequency of individual features may have been overemphasized in the past, and that a minority of patients may exist who are clinically indistinguishable from WBS but who appear to have no deletion at 7q11.

Isochromosome 18p results from maternal meiosis II nondisjunction.

Microsatellite analysis with 13 microsatellites spread over 18p was performed to determine the origin of the marker chromosome in 9 patients with additional metacentric marker chromosomes. Phenotypes and banding patterns suggested that the markers were isochromosomes 18p. Maternal origin was determined in all 8 cases where both parents were available for study. Six cases showed 3 alleles (one paternal, one maternal each in single and double dose) of informative markers located close to the telomere while markers close to the centromere on 18p were reduced to homozygosity (one paternal allele in single dosage and one maternal allele presumably in triple dosage). A similar result was obtained in the patient with no parents available for examination. The other 2 patients were uninformative for maternal hetero- versus homozygosity, but at some loci the maternal band was clearly stronger than the paternal one whereas the opposite was never observed. Trisomy 18 differs from trisomy 21, XXX and XXY of maternal origin through a preponderance of meiosis II versus meiosis I nondisjunction. Thus, the results of our study and the advanced mean maternal age at delivery of patients with additional i(18p) indicate that in most if not all cases the marker chromosome originates from maternal meiosis II nondisjunction immediately followed by isochromosome formation in one of the 2 maternal chromosomes 18. Possible explanations of these results include a maternally imprinted gene on 18q with a lethal effect if the paternal homologue is lost and a mechanism through which nondisjunction in some cases could be connected with isochromosome formation.