Jaime Garcia-Heras

De novo partial duplications 1p: report of two new cases and review.

We describe two de novo intrachromosomal duplications of 1p. One case is a dir ins dup(1)(q21p21p31) in a newborn girl with low birth weight, growth retardation, and tetralogy of Fallot. The other is a 10-month-old girl with developmental delay, craniosynostosis, plagiocephaly, and an inv dup 1p34.1p31. Although, these patients have manifestations in common with previous cases, they do not establish a syndrome. Interestingly, all males with duplications spanning 1p31 had genital anomalies, whereas females with duplications of the same region had normal genitalia. Thus, genes within 1p31 appear to control the development of male genitalia and tentatively exclude effects of tda1, a sex-determining gene in a region of mouse chromosome 4 syntenic to 1p36 in man. However, it is necessary to identify the human tda1 homologue and candidate genes within 1p31 before drawing final conclusions.

Constitutional del(19) (q12q13.1) in a three-year-old girl with severe phenotypic abnormalities affecting multiple organ systems

We present the clinical, cytogenetic, and molecular studies on a constitutional deletion of 19q ascertained prenatally due to decreased fetal activity and IUGR. Chromosome analysis by GTG banding on amniocytes suggested a del(19)(q13.1q13.3), but the analysis of microsatellites by PCR demonstrated that the deletion involved the distal segment of q12 and the proximal segment of q13.1 (15 cM). The severely affected female infant born at 38 weeks has clinical findings that may be related to haploinsufficiency of specific genes within 19q12.1-->q13.1 that control important processes of normal development and cell function.

De novo der(X)t(X;10)(q26;q21) with features of distal trisomy 10q: case report of paternal origin identified by late replication with BrdU and the human androgen receptor assay (HAR).

We describe an 11 year old girl with a de novo unbalanced t(X;10) that resulted in a deletion of Xq26-->Xqter and a trisomy of 10q21-->10qter. Her clinical features were of distal trisomy 10q, but she lacked the cardiovascular and renal malformations observed in duplications of 10q24-->10qter and had only moderate mental retardation. X inactivation was assessed on peripheral blood lymphocytes by late replication with BrdU (LR) and the human androgen receptor assay (HAR). By LR the der(X) was inactive without spreading to 10q21-->10qter in all cells. The HAR assay showed skewed methylation of the paternal allele (90%). The correlation of HAR and LR suggests that the der(X) was paternally inherited and is consistent with data from other de novo balanced and unbalanced X;autosome translocations detected in females. This is the first report of parental origin of a de novo trisomy 10q.

Prenatal diagnosis of a trisomy 17p derived from a de novo non-mosaic satellited marker

A trisomy 17pter→p11.2 derived from a supernumerary de novo satellited marker was identified by GTG bands and fluorescent in situ hybridisation (FISH) in amniocytes of a fetus with malformations and intrauterine growth retardation (IUGR). At 39 weeks a male infant with a phenotype similar to other postnatal cases of ‘pure.’ complete trisomy 17p was born. Some additional clinical features, however, make him more severely affected than previous patients.

'De novo' duplication Xq23→Xq26 of paternal origin in a girl with a mildly affected phenotype

We report a de novo dup(X)(q23-->q26) in a 3-year-old girl with growth retardation, developmental delay, and minor anomalies. X-inactivation in lymphocytes by BRDU labeling showed the abnormal X was late replicating. The androgen receptor assay (HAR) demonstrated a skewed methylation (88.8%) of the paternal allele and a 11.2% methylation of the maternal allele. These data, which suggest the duplication was paternally inherited, are the first parental-origin identification of a duplication Xq. The mild phenotype of the patient may be related to the size and region of the duplication, the low percentage of a dup(X) active detected by the HAR assay, or a combination of these mechanisms.

Prenatal diagnosis of a de novo trisomy 6q22.2→6qter and monosomy lpter→1p36.3. Case report with a 2‐year follow‐up and a brief review of other prenatal cases of partial trisomy 6q

We report a de novo trisomy 6q22.2→6qter and monosomy lpter→1p36.3 identified in amniocytes by GTG banding and FISH. While ultrasonography demonstrated malformations that did not suggest a specific chromosomal syndrome, a male infant with features consistent with trisomy 6q was born. He was followed up until 23 months, when he died after cardiac surgery. The only two other prenatal cases of trisomy 6q were compared with our patient. A literature review showed that trisomy 6q has not been reported in association with the anomalies seen by ultrasound in this case.

A brief review of cryptic duplications of 21q as an emerging cause of Down syndrome: practical considerations for accurate detection

We review five cryptic duplications of 21q in patients with Down syndrome (DS) that were inherited from parental balanced translocations. All cases were identified by fluorescence in situ hybridization (FISH) and/or DNA diagnosis because the phenotype was inconsistent with the initial cytogenetic studies. These rearrangements seem to escape detection without expanded testing and are probably more frequent than expected. For this reason we propose a series of steps combining objective clinical diagnostic criteria, FISH and DNA methods to achieve an accurate ascertainment.

Prenatal diagnosis of a der(X)t(X;15)(p22.2;q11.2) inherited from a maternal translocation X;15

A karyotype 46,X,der(X)t(X;15)(p22.2;q11.2) derived from a maternal translocation X;15 was ascertained in a female fetus through an abnormal triple screen test at 16 weeks that gave a 1/56 risk for Down syndrome. The pregnancy was terminated at 19·5 weeks and anatomopathologic studies showed fewer malformations than other fetal trisomies 15. This is the first prenatal identification of an unbalanced t(X;15).

Familial translocation (X;3)(p22.3;p23): chromosomal in situ suppression (CISS) hybridization and inactivation pattern study

To the Editor: Bettio et al. reported an unbalanced X/3 translocation which was maternally inherited and resulted in a monosomy Xp22.3+Xpter and a trisomy 3p23+3pter in a child with few features of trisomy 3p (slight hypotonia, epicanthic folds, a transverse palmar crease on the right hand and a congenital heart defect). The der(X) was late replicating without inactivation spreading to the autosome in lymphocytes and fibroblasts. This milder phenotype was considered an underexpressed trisomy 3p because the X chromosome was involved in an unbalanced translocation compared to unequal autosomal exchanges which would have a full phenotype (Bettio et al. 1994). Since patients with partial trisomy 3p2 are usually significantly affected (Conte et al. 1995), I would like to propose a hypothesis for the mild pheno,type of this case which was not discussed in this paper. Some unbalanced Wautosome translocations with fewer manifestations than expected for the autosomal trisomy have shown late replication of the derivative X that spreads over a variable length into the autosome. Even if complete spreading occurred in only a few cells, it was probably sufficient to attenuate the phenotype (Zuffardi et al. 1977, Morichon-DelVallez et al. 1982, Rivera et al. 1984, Caiulo et al. 1989, Kulharya et al. 1995). In this proband the discordance between late replication and the attenuated phenotype could be due to a “cryptic” spreading of inactivation to 3p23+3pter or a reactivation of this previously inactive region. The “cryptic” inactivation of the whole der(X) might be present in a small population of fibroblasts