Prawdopodobieństwo wystąpienia różnych patologii ciąży w rodzinach nosicieli translokacji chromosomowych wzajemnych angażujących chromosom 13

Summary Objectives: The aim of study was to estimate the probability rates for unfavorable pregnancy outcomes in carriers of reciprocal chromosomal translocations involving 13 chromosome (RCT-13q). Material and methods: We collected total empirical data about 232 pregnancies of 56 carriers coming from 28 pedigrees. RCT classification was based on classic cytogenetic methods for interpretation of breakpoint position. The probability rates of particular type of pathology related to the total number of pregnancies after ascertainment correction have been calculated with the help of Stengel-Rutkowski and Stene method. Results: The risk figures for unbalanced offspring after 2:2 disjunction and adjacent-1 segregation for the whole group of pedigrees were calculated as 5.2+/-1.7% (9/173) – medium risk, for maternal (MAT) and paternal (PAT) carriers were about 6.2+/-2.3% (7/173) and 4.8+/-3.3% (2/42) respectively. Considering different segment lengths of 13q, similar values for shorter and longer segments were obtained [4.3+/-1.9% (5/115) for 13q21→qter and 7.0+/-3.3% (4/58) for 13q12→qter]. The risk figures for miscarriages as 36.4+/-3.6% (63/173) and for stillbirths/early death as 4.6+/-31.6% (8/173) were obtained. The risk figures for unbalanced offspring after 3:1 disjunction were calculated as 7.7+/-7.45 (9/13). Conclusions: 1. Risk figures for different pregnancy outcomes are differ among particular forms of pathology 2. Probability rate for unbalanced progeny at birth was calculated as a medium risk and similar values for carriers of different segments of 13q were obtained 3. Probability rate for miscarriages was high but risk for stillbirths/early deaths of newborn was low 4. No differences in values of rate for particular forms of pathology were found for maternal and paternal carriers of RCT -13q.Streszczenie Cel pracy: Celem badań było oszacowanie prawdopodobieństwa wystąpienia różnych patologii ciąży w rodzinach nosicieli translokacji chromosomowych wzajemnych angażujących długie ramię chromosomu 13 (TCW-13q). Materiał i metody: Materiał do analizy stanowiły dane empiryczne i cytogenetyczne o 232 ciążach 56 nosicieli, uzyskane z 28 rodowodów nosicieli TCW ryzyka pojedynczego niezrównowaęenia segmentu angażujących chromosom 13. Prawdopodobieństwo wystąpienia różnych patologii ciąży oszacowano metodą Stengel-Rutkowski i Stene. Wyniki: Prawdopodobieństwo urodzenia dziecka z niezrównoważonym kariotypem w rodzinach nosicieli TCW z udziałem chromosomu 13 po segregacji 2:2 rozdziale przyległym typu 1 wynosiło 5,2+/-1,7% (9/173) – ryzyko średnie; po segregacji 3:1 ryzyko wynosiło 7,7+/-7,4% (9/13) – ryzyko średnie. W przypadku nosicielstwa matczynego (MAT) osiągnęło wartość 6,2+/-2,3% (7/173), zaś ojcowskiego (PAT) wartość 4,8+/-3,3% (2/42). Rozpatrując poszczególne segmenty chromosomu 13, prawdopodobieństwo miało następujące wartości: segment 13q21.2→qter - 4,3+/-1,9% (5/115), segment 13q12→qter – 7+/-3,3% (4/58). Ryzyko utraty ciąży na skutek ciąż obumarłych określono na 4,6+/-1,6% (8/173), natomiast ryzyko poronień samoistnych 36,4+/-3,6% (63/173). Wnioski: 1. Wielkości prawdopodobieństwa wystąpienia poszczególnych patologii ciąży w rodzinach nosicieli TCW-13q są różne. 2. Wielkość prawdopodobieństwa urodzenia dziecka z niezrównoważonym kariotypem należy do grupy ryzyka średniego; uzyskano podobne wartości w rodzinach nosicieli poszczególnych segmentów chromosomu 13. 3. Wielkość ryzyka genetycznego poronień samoistnych należy do grupy ryzyka wysokiego i jest wyższe w stosunku do ryzyka ciąż obumarłych przed terminem porodu (grupa ryzyka niskiego). 4. Nie stwierdzono różnic w wielkości wskaźników ryzyka dla poszczególnych form patologii ciąży w zależności od płci nosiciela

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

Maternal uniparental disomy for the entire chromosome 7 has so far been reported in three patients with intrauterine and postnatal growth retardation. Two were detected because they were homozygous for a cystic fibrosis mutation for which only the mother was heterozygous, and one because he was homozygous for a rare COL1A2 mutation. We investigated 35 patients with either the Silver-Russell syndrome or primordial growth retardation and their parents with PCR markers to search for uniparental disomy 7. Four of 35 patients were found to have maternal disomy, including three with isodisomy and one with heterodisomy. The data confirm the hypothetical localization of a maternally imprinted gene (or more than one such gene) on chromosome 7. It is suggested to search for UPD 7 in families with an offspring with sporadic Silver-Russell syndrome or primordial growth retardatio

Ocena prawdopodobieństwa urodzenia dziecka z niezrównoważonym kariotypem oraz ryzyka wystąpienia rożnych patologii ciąży w rodzinach nosicieli translokacji chromosomowych wzajemnych angażujących chromosom 7

Introduction: Carriership of reciprocal chromosomal translocation (RCT) may be the reason the occurrence of congenital malformations in the offspring, early neonatal death, stillbirth, and recurrent miscarriages due to unbalanced karyotype of gametes. The probability rate for individual categories of unfavorable outcomes depends on the kind of chromosome involved and is individually variable. Objectives: The aim of study was to estimate the probability rates for unbalanced offspring and to evaluate the risk for different categories of unfavorable pregnancy outcomes, depending on the size of chromosomal segment with differentiation between maternal/paternal origin of the reciprocal chromosomal translocations involving chromosome 7p (RCT-7p) and 7q (RCT-7q). In addition, the use of the obtained results has been illustrated by the example of a family with unique RCT t(7;9)(p21.3,p23). Material and methods: Empirical and cytogenetic data on 341 pregnancies and offspring of 133 carriers were collected from 69 pedigrees of carriers of RCT-7p and RCT-7q at risk for a single 7 segment imbalance. The probability rates of particular form of pregnancy pathology have been calculated according to the method of Stengel-Rutkowski and Stene, including all forms of meiotic segregation and their survival rates after fertilization to term childbirth. Results: The probability rates for unbalanced offspring for carriers of RCT-7p after 2:2 disjunction and adjacent-1 segregation were calculated as 5.5%±2.2% (6/108); for maternal (MAT) and paternal (PAT) carriers were aboutCel pracy: Celem pracy było opracowanie wskaźników prawdopodobieństwa urodzenia dziecka z niezrównoważonym kariotypem oraz wskaźników ryzyka różnych patologii ciąży w rodzinach nosicieli translokacji chromosomowych wzajemnych angażujących segmenty chromosomu 7 (TCW-7), w zależności od długości pojedynczych segmentów krótkich (TCW-7p) i długich (TCW-7q) ramion chromosomu 7, z uwzględnieniem rodzicielskiego pochodzenia nosicielstwa. Na przykładzie rodziny z nosicielstwem unikatowej t(7;9)(p21.3;p23) zaprezentowano, w jaki sposób praktycznie można wykorzystać uzyskane wskaźniki udzielając porady genetycznej. Materiał i metody: Analizę segregacyjną przeprowadzono w grupie 69 rodowodów nosicieli TCW-7 zawierających dane kliniczne i cytogenetyczne 341 ciąż i urodzeń potomstwa w sześciu grupach oddzielnie w zależności od długości segmentu 7p i 7q wyznaczonej przez położenie punktu złamania TCW: 7p21→pter, 7p14…p15→pter, 7p11…p12…p13→pter oraz 7q33…q34…q35→qter, 7q32 →qter, 7q11…q21.. q22…q31→qter z uwzględnieniem rodzicielskiego pochodzenia TCW. Wyniki: Prawdopodobieństwo urodzenia dziecka z niezrównoważonym kariotypem w przypadku nosicielstwa TCW-7p wynosiło 5.5±2.2% (6/108) (w tym matczyne MAT

No evidence of uniparental disomy 2, 6, 14, 16, 20, and 22 as a major cause of intrauterine growth retardation

Intrauterine growth retardation (IUGR) is defined as length and/or weight below the 10th percentile. Etiology and, consequently, long-term outcome are extremely heterogeneous with chromosomal abnormalities found in up to 7%. Recently, uniparental disomy (UPD), i.e. the inheritance of both homologues of one pair of chromosomes from only one parent, was found in an increasing number of children with IUGR. Particularly, UPD of chromosome 7 was found in up to 10% of patients with IUGR and/or a phenotype of primordial growth retardation or Silver-Russell syndrome (SRS), but also UPD of chromosomes 2, 6, 14, 16, 20, and 22 was reported in single cases with IUGR. To evaluate impact and relevance of UPD in children with IUGR we investigated 23 sporadic cases with IUGR subsequently diagnosed as primordial growth retardation (n=13) or SRS (n=10) by molecular methods for UPD of chromosomes 2, 6, 14, 16, 20, and 22. No instance of UPD was found. Inheritance of all chromosomes investigated was biparental in all cases. Therefore, we conclude that UPD of these chromosomes is not a major cause of IUGR

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. Conclusion This 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

Trisomy 2p: Analysis of unusual phenotypic findings

We present three probands with partial trisomies 2p21-23 due to ins(4;2)(q21;p21p23) pat, 2p23-pter due to t(2;4)(p23;q35)mat, and 2p21-pter due to t(2;11)(p21;q23.3)mat. More than 50 cases of partial trisomy 2p have been reviewed and some abnormalities, unusual for most other types of structural autosomal imbalance, have been found in patients with inherited forms of 2p trisomy and in their non-karyotyped sibs. Neural tube defects (anencephaly, occipital encephalocele, and spina bifida) were found in five probands and 4/6 affected non-karyotyped sibs. The only triplicated segment common to all was 2p24. Different forms of "broncho-pulmonary a/hypoplasia" (including two cases of lung agenesis) were described in four patients (overlapping triplicated segment was 2p21-p25). Three patients (with overlapping triplicated segment 2p23-p25) had diaphragmatic hernia. Abnormal rotation of the heart or L-transposition of large vessels (with or without visceral heterotaxia) was found in two infants (overlapping triplicated segment 2p23-p24). In two patients with common triplicated segment 2p22.3-p25, neuroblastoma has been described. The occurrence of all these defects may be explained either by the action of the same gene(s) mapped to 2p24 or by action of some independent factors located in different segments of the short arm. Although the latter hypothesis is much less probable, it can not be rejected at the present time. We propose the existence of a genetic system controlling surveillance of an abnormal embryo to explain the phenotypic differences between patients with the same imbalance within a family. In some "restrictive" combinations the abnormal embryos will die, although in "permissive" combinations they can survive

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

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

4q32–q35 and 6q16–q22 are valuable candidate regions for split hand/foot malformation

On the basis of the Human Cytogenetic Database, a computerized catalog of the clinical phenotypes associated with cytogenetically detectable human chromosome aberrations, we collected from the literature 102 cases with chromosomal aberrations and split hand/foot malformation or absent fingers/toes. Statistical analysis revealed a highly significant association (P<0.001) between the malformation and the chromosomal bands 4q32–q35, 5q15, 6q16–q22 and 7q11.2–q22 (SHFM1). Considering these findings, we suggest additional SHFM loci on chromosome 4q, 6q and probably 5q. The regions 4q and 6q have already been discussed in the literature as additional SHFM loci. We now show further evidence. In the proposed regions, there are interesting candidate genes such as, on 4q: HAND2, FGF2, LEF1 and BMPR1B; on 5q: MSX2, FLT4, PTX1 and PDLIM7; and on 6q: SNX3, GJA1, HEY2 and Tbx18

Chromosomal map of human brain malformations

The etiology of most central nervous system (CNS) malformations remains unknown. We have utilized the fact that autosomal chromosome aberrations are commonly associated with CNS malformations to identify new causative gene loci. The human cytogenetic database, a computerized catalog of the clinical phenotypes associated with cytogenetically detectable human chromosome aberrations, was used to identify patients with 14 selected brain malformations including 541 with deletions, and 290 carrying duplications. These cases were used to develop an autosomal deletion and duplication map consisting of 67 different deleted malformation associated bands (MABs) in 55 regions and 88 different duplicated MABs in 36 regions; 31 of the deleted and 8 duplicated MABs were highly significantly associated (P < 0.001). All holoprosencephaly MABs found in the database contained a known HPE gene providing some level of validation for the approach. Significantly associated MABs are discussed for each malformation together with the published data about known disease-causing genes and reported malformation-associated loci, as well as the limitations of the proposed approach