Beata Stasiewicz-Jarocka

Interstitial deletion 9q22.32-q33.2 associated with additional familial translocation t(9;17)(q34.11;p11.2) in a patient with Gorlin–Goltz syndrome and features of Nail-Patella syndrome

The phenotype of Gorlin–Goltz syndrome or basal cell nevus syndrome (BCNS, #109400, OMIM), a Mendelian trait due to PTCH mutations has been reported in a few cases of interstitial deletion of chromosome 9q. We present an 11‐year‐old girl with clinical features consistent with BCNS including bridging of sella turcica, biparietal bossing, downward slanting palpebral fissures, mandible prognathism, pectus excavatum, thumb abnormalities, occult spina bifida at L5‐S4, numerous basal cell nevi, and single basal cell carcinoma. Cytogenetic analysis using high‐resolution banding techniques and fluorescence in situ hybridization (FISH) revealed interstitial chromosome deletion 9q22.32‐q33.2 involving the PTCH gene as a secondary breakage event to a chromosome translocation t(9;17)(q34.1;p11.2)mat. Further FISH studies showed the translocation breakpoint on 9q34.11 maps proximal to ABL, between the BAC clone RP11‐88G17 and the LMX1B gene. The latter gene encodes a transcription factor, in which loss of function mutations are responsible for the nail‐patella syndrome (NPS, #161200 OMIM). Interestingly, some features of our proband (e.g., bilateral patellar dysplasia and abnormal clavicular shape), as well as her healthy sister who carries the same translocation, are also found in patients with NPS. The chromosome 17p11.2 breakpoint maps in the Smith‐Magenis syndrome common deletion region, within two overlapping BAC clones, CTD‐2354J3 and RP11‐311F12.

Genetic counseling in carriers of reciprocal chromosomal translocations involving long arm of chromosome 16

Families with balanced chromosomal changes ascertained by unbalanced progeny, miscarriages, or by chance are interested in their probability for unbalanced offspring and other unfavorable pregnancy outcomes. This is usually done based on the original data published by Stengel‐Rutkowski et al. several decades ago. That data set has never been updated. It is particularly true for the subgroup with low number of observations, to which belong reciprocal chromosomal translocations (RCTs) with breakpoint in an interstitial segment of 16q. The 11 pedigrees from original data together with the new 18 pedigrees of RCT carriers at risk of single‐segment imbalance detected among 100 pedigrees of RCT carriers with breakpoint position at 16q were used for re‐evaluation of the probability estimation for unbalanced offspring at birth and at second trimester of prenatal diagnosis, published in 1988. The new probability rate for unbalanced offspring after 2u2003:u20032 disjunction and adjacent‐1 segregation for the total group of pedigrees was 4u2003±u20033.9% (1/25). In addition, the probability estimate for unbalanced fetuses at second trimester of prenatal diagnosis was calculated as 2/11, i.e. 18.2u2003±u200311.6%. The probability rates for miscarriages and stillbirths/early deaths were about 16u2003±u20037.3% (4/25) and <2% (0/25), respectively. Considering different segment lengths of 16q, higher probability rate (0/8, i.e. <6.1%) for maternal RCT carriers at risk of distal 16q segment imbalance (shorter segment) was obtained in comparison with the rate (0/10, i.e. <4.8%) for RCT at risk of proximal segment imbalance (longer segment). It supports findings obtained from the original data for RCT with other chromosomes, where the probability for unbalanced offspring generally increased with decreasing length of the segments involved in RCT. Our results were applied for five new families with RCT involving 16q, namely three at risk of single‐segment imbalance [t(8;16)(q24.3;q22)GTG, ish(wcp8+,wcp16+;wcp8–,wcp16+), t(11;16)(q25;q22)GTG, and t(11;16)(q25;q13)GTG] and two with RCT at risk of double‐segment imbalance [t(16;19)(q13;q13.3)GTG, isht(16;19)(q13;q13.3) (D16Z3+,16QTEL013−D19S238E+,TEL19pR–; D16Z3−, D19S238E–,TEL19pR+), and t(16;20)(q11.1;q12)GTG, m ish,t(16;20)(wcp16+,wcp20+;wcp16+,wcp20+)]. They have been presented in details to illustrate how the available empiric data could be used in practice for genetic counseling.

Complex balanced chromosomal translocation t(2;5;13) (p21;p15;q22) in a woman with four reproductive failures.

BackgroundBalanced complex translocations (BCTs) are rare events, they may result in reproductive failures: spontaneous abortions, missed abortions, stillbirths, congenital malformations in children, and male infertility. BCTs belong to the group of complex chromosome rearrangements (CCRs) – up to date about 260 cases were described.ResultsThe described patient and her husband were referred to genetic counseling clinic because of four reproductive failures. GTG-banded chromosome analysis revealed presence of apparently balanced complex translocation t(2;5;13), which was verified and confirmed by molecular cytogenetics with single copy probes. This complex aberration was most likely responsible for reproductive failures in our patient. Since no high resolution molecular karyotyping (microarrays) was used, this rearrangement can only be considered to be balanced at cytogenetic level.DiscussionDue to small number of reported cases of CCRs/BCTs and individual as well as unique character of such rearrangements, genetic counseling for CCRs carriers is complex and requires detailed pedigree analysis, as well as extended clinical and genetic testing.

Recurrence risks for different pregnancy outcomes and meiotic segregation analysis of spermatozoa in carriers of t(1;11)(p36.22;q12.2)

Cumulative data obtained from two relatively large pedigrees of a unique reciprocal chromosomal translocation (RCT) t(1;11)(p36.22;q12.2) ascertained by three miscarriages (pedigree 1) and the birth of newborn with hydrocephalus and myelomeningocele (pedigree 2) were used to estimate recurrence risks for different pregnancy outcomes. Submicroscopic molecular characterization by fluorescent in situ hybridization (FISH) of RCT break points in representative carriers showed similar rearrangements in both families. Meiotic segregation patterns after sperm analysis by three-color FISH of one male carrier showed all possible outcomes resulting from 2:2 and 3:1 segregations. On the basis of empirical survival data, we suggest that only one form of chromosome imbalance resulting in monosomy 1p36.22ue232pter with trisomy 11q12.2ue232qter may be observed in progeny at birth. Segregation analysis of these pedigrees was performed by the indirect method of Stengel-Rutkowski and showed that probability rate for malformed child at birth due to an unbalanced karyotype was 3/48 (6.2±3.5%) after ascertainment correction. The risk for stillbirths/early neonatal deaths was −/48 (<1.1%) and for miscarriages was 17/48 (35.4±6.9%). However, the probability rate for children with a normal phenotype at birth was 28/48 (58.3±7.1%). The results obtained from this study may be used to determine the risks for the various pregnancy outcomes for carriers of t(1;11)(p36.22;q12.2) and can be used for genetic counseling of carriers of this rearrangement.

A 23-year follow-up of a male with Hajdu-Cheney syndrome due to NOTCH2 mutation

We present a natural history of a 32‐year‐old man with Hajdu‐Cheney syndrome (HJCYS), because of the de novo truncating mutation in the exon 34 of NOTCH2 (c.6424‐6427delTCTG, p.Ser2142ArgfsX4), who has been followed up for a period of 23u2009years (between 9 and 32u2009years). During follow‐up, we observed abnormalities of vision, hearing, voice, and progression of craniofacial features in the form of skeletal dysplasia with affected skull, dentition, spine, limbs, fingers, and toes. Low bone mineral density and history of fragility fractures also suggested primary osteoporosis being a clinical manifestation. According to Stengel‐Rutkowski, Schimanek, and Wernheimer (1984; Human Genetics, 6, 272–295), systematic data acquisition has been used for quantitative analysis of anthropological, radiographic, and clinical features at childhood, adolescence, and young adulthood separately. A detailed phenotype description together with the results of reanalysis of 14 reports so far published on patients with HJCYS and NOTCH2 mutation showed similar phenotype evolution with age. The spectrum of observed features may improve diagnostic tools for HJCYS at different periods of the lifespan.

Limited survivability of unbalanced progeny of carriers of a unique t(4;19)(p15.32;p13.3): a study in multiple generations

BackgroundCarriership of a reciprocal chromosomal translocation (RCT) involving the short arm of chromosome 4 (4p) may result in birth of a child with Wolf-Hirschhorn syndrome (WHS) due to monosomy 4p, a priori modified by the impact of the partner chromosome imbalance. Familial transmission studies of RCT enable obtaining empirical risk figures that are essential for genetic counseling. In this study, pedigree data from carriers of a unique t(4;19)(p15.32;p13.3), ascertained by two children with WHS phenotype, were collected through five generations and empirical risk for different pregnancy outcomes was assessed. In addition, the phenotype-karyotype correlation was studied in two unbalanced children against the phenotypes of children (literature data) with pure monosomy 4p15.32xa0→xa0pter and pure trisomy 19p13.3xa0→xa0pter, accordingly. The phenotype analysis was conducted using the catalogue of traits according to the Munich Dysmorphology Database. Pedigree segregation analysis was conducted by the direct method according to Stengel- Rutkowski et al.ResultsA double segment imbalance, trisomy 19p13.3xa0→xa0pter with monosomy 4p15.32xa0→xa0pter, was diagnosed in WHS progeny at birth. No essential modification of WHS phenotype by the additional trisomy 19p was observed, except for a limited survivability (death in infancy). Pedigree segregation analysis covered 39 relatives showed the probability rate for liveborn with unbalanced karyotype of 3.7xa0±xa03.6% (1/27), for stillbirth/neonatal death at 7.4xa0±xa05.0% (2/27), for miscarriage at 22.2xa0±xa08.0% (6/27), for the chance of having a baby without unbalanced karyotype was estimated at 66.7xa0±xa09.1% (18/27). In addition, the value of 7.4% for genetic counseling for any carrier of RCT at risk for single segment 19p13.3xa0→xa0pter imbalance at birth was evaluated as such value have not been estimated so far.ConclusionCarriership of a t(4;19)(p15.32;p13.3) is at low risk for an unbalanced child at birth and for stillbirth/neonatal death but high for miscarriages. The chance of having a baby without unbalanced karyotype was estimated to be high. Monosomy 4p15.32xa0→xa0pter together with trisomy 19p13.3xa0→xa0pter as a double segment imbalance in children with WHS may be connected with a limited survivability in infancy.