Disease associated balanced chromosome rearrangements (DBCR): report of two new cases.

Disease associated balanced chromosome rearrangements (DBCR) causing truncation, deletion, inactivation or over-expression of specific genes are instrumental in identifying and cloning several disease genes and are estimated to be much more common than anticipated. In one survey, the minimal frequency of combined balanced de novo reciprocal translocations and inversions causing abnormal phenotype is estimated to be 0.17%, a sixfold increase compared to the general population suggesting a causative linkage between the abnormality and the observed phenotypic traits. Here, we report two new cases of apparently balanced de novo translocations resulting in developmental delay and dysmorphic features.

De novo supernumerary ring chromosome 7: first report of a non-mosaic patient and review of the literature.

The present authors report the case of a 12-year-old-boy with a de novo, non-mosaic supernumerary ring chromosome 7 associated with significant developmental delay and speech difficulty. A review of the literature identified a total of 18 cases with ring chromosomes 7 who can be classified into two groups: (1) patients with a cell line that has 47 chromosomes with a small supernumerary ring chromosome 7 resulting in partial trisomy; and (2) individuals had a cell line with a large ring chromosome replacing one of the normal chromosomes 7 resulting in partial monosomy. A comparison of clinical features in the two groups of patients showed several common features such as growth and mental retardation, and facial dysmorphism, including, ear and eye anomalies. However, patients with partial trisomy have speech difficulty as a distinguishing feature, while patients with partial monosomy have skin lesions as a cardinal feature. All the published cases of ring chromosome 7, irrespective whether they are supernumerary or normal modal number, are mosaics except for one. The present subject is the first case of a de novo, non-mosaic supernumerary ring chromosome 7.

Ring chromosome 8 syndrome: further characterization.

We describe two de novo cases of extra r(8) confirmed by fluorescent in situ hybridization (FISH). Based on these two and eight additional cases of extra r(8) confirmed by FISH, the phenotype is better documented. One of our patients had minor facial anomalies, near-normal growth, and neurological development. She had a ring in each cell analyzed. The second had minor craniofacial anomalies and growth and mental retardation. He had a small or double-sized ring in each cell. The phenotype of these 10 cases ranges from almost normal in an adult with 10% mosaicism to variable degrees of minor anomalies, growth retardation, and mental retardation overlapping the mosaic +8 syndrome.

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.

Mutation analysis of UBE3A in Angelman syndrome patients.

Angelman syndrome (AS) is caused by chromosome 15q11-q13 deletions of maternal origin, by paternal uniparental disomy (UPD) 15, by imprinting defects, and by mutations in the UBE3A gene. UBE3A encodes a ubiquitin-protein ligase and shows brain-specific imprinting. Here we describe UBE3A coding-region mutations detected by SSCP analysis in 13 AS individuals or families. Two identical de novo 5-bp duplications in exon 16 were found. Among the other 11 unique mutations, 8 were small deletions or insertions predicted to cause frameshifts, 1 was a mutation to a stop codon, 1 was a missense mutation, and 1 was predicted to cause insertion of an isoleucine in the hect domain of the UBE3A protein, which functions in E2 binding and ubiquitin transfer. Eight of the cases were familial, and five were sporadic. In two familial cases and one sporadic case, mosaicism for UBE3A mutations was detected: in the mother of three AS sons, in the maternal grandfather of two AS first cousins, and in the mother of an AS daughter. The frequencies with which we detected mutations were 5 (14%) of 35 in sporadic cases and 8 (80%) of 10 in familial cases.

Prenatal diagnosis of a de novo trisomy 6q22.2-->6qter and monosomy 1pter-->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 trisom 6q22.2-->6qter and monosomy 1pter-->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 second autosomal split hand/split foot locus maps to chromosome 10q24-q25.

Ectrodactyly (split hand/split foot malformation, SHSF) is a human limb malformation characterized by absent central digital rays, deep median cleft, and syndactyly of remaining digits. The disorder is genetically heterogeneous, with at least two loci thus far determined: an autosomal locus at 7q21 designated SHFM1 and an X-linked locus at Xq26 designated SHFM2. Cytogenetic analysis of sporadic SHSF patients and linkage studies in extended pedigrees both suggest more than one autosomal locus exists. We report a novel SHSF locus suggested by a stillborn infant with ectrodactyly and other malformations who inherited an unbalanced translocation resulting in monosomy 4p15.1-4pter and trisomy for 10q25.2-qter. To investigate 10q25 as a possible split hand/split foot locus, microsatellite markers spanning 52 cM of 10q were utilized for linkage analysis of a large autosomal dominant SHSF pedigree in which the region encompassing SHFM1 previously was excluded as containing the causative mutation. The marker D10S583 was fully informative in the family, giving a maximum LOD score of 4.21 at recombination theta = 0.00. Recombination haplotypes define the 9 cM region between D10S541 and D10S574 as inclusive for this second autosomal SHSF locus, for which we propose the designation SHFM3.

Mild phenotypic effects of a de novo deletion Xpter-->Xp22.3 and duplication 3pter-->3p23.

We report on a girl with a de novo monosomy Xpter-->Xp22.3 and trisomy 3pter-->3p23, normal development and stature, mildly affected phenotype, and learning disabilities with a low normal level of intelligence. Late replication studies using BudR demonstrated that the entire der(X) was inactive in 30% of cells. In 62% of cells the inactivation did not spread to the autosomal segment in the der(X). The normal X was inactivated in 8% of cells. Quantitative X-inactivation studies using the human androgen receptor locus assay (HAR) on peripheral leukocytes and buccal epithelial cells showed extreme skewing of methylation (90.4% of the paternal allele). The correlation of cytogenetic and molecular data suggest that the mild phenotype of the proposita is most likely due to preferential inactivation of the entire der(X), which seems to be of paternal origin.

Interstitial deletions 4q21.1q25 and 4q25q27: phenotypic variability and relation to Rieger anomaly.

We describe clinical and chromosomal findings in two patients with del(4q). Patient 1, with interstitial deletion (4)(q21.1q25), had craniofacial and skeletal anomalies and died at 8 months of hydrocephalus. Patient 2, with interstitial deletion (4)(q25q27), had craniofacial and skeletal anomalies with congenital hypotonia and developmental delay. These patients shared certain manifestations with other del(4q) patients but did not have Rieger anomaly. Clinical variability among patients with interstitial deletions of 4q may be related to variable expression, variable deletion, or imprinting of genes within the 4q region.

Evidence for locus heterogeneity in human autosomal dominant split hand/split foot malformation.

Split hand/split foot (SHSF; also known as ectrodactyly) is a human developmental disorder characterized by missing central digits and other distal limb malformations. An association between SHSF and cytogenetically visible rearrangements of chromosome 7 at bands q21-q22 provides compelling evidence for the location of a causative gene at this location, and the locus has been designated SHFD1. In the present study, marker loci were localized to the SHFD1 critical region through the analysis of somatic cell hybrids derived from individuals with SHSF and cytogenetic abnormalities involving the 7q21-q22 region. Combined genetic and physical data suggest that the order of markers in the SHFD1 critical region is cen-D7S492-D7S527-(D7S479-D7S491)-SHFD1-++ +D7S554-D7S518-qter. Dinucleotide repeat polymorphisms at three of these loci were used to test for linkage of SHSF to this region in a large pedigree that demonstrates autosomal dominant SHSF. Evidence against linkage of the SHSF gene to 7q21-q22 was obtained in this pedigree. Therefore, combined molecular and genetic data provide evidence for locus heterogeneity in autosomal dominant SHSF. We propose the name SHSF2 for this second locus.

Tetrasomy 9p: an emerging syndrome.

An infant with non-mosaic 9p tetrasomy is described. The tetrasomy apparently results from a translocation involving the 9qh region. All the cells analyzed from multiple banding techniques from lymphocyte culture as well as skin fibroblast culture were 9p tetrasomic. The infant, who had the characteristic dysmorphic features of 9p tetrasomy, survived for 2 months. Prominent features included: low birth weight, severe retardation, brachycephaly with large anterior fontanelle, hypertelorism with short bilateral palpebral fissures, beaked nose, bilateral cleft lip and palate, and low-set, malformed ears. Skeletal anomalies, ambiguous genitalia and heart defect were also observed. These features are highly characteristic of the 9p tetrasomy syndrome based on six pure tetrasomy and four cases of tetrasomy that included part of the 9qh region.

Euchromatic 16p+ heteromorphism: first report in North America.

A heteromorphism of the short arm of 16 (16p+) was discovered in 2 unrelated infants. By G banding, the euchromatic variant appears as a light and a medium dark band just distal to the centromere. This results in an increase of the short arm by about 1/3. The same variant was present in the normal father and the normal paternal grandmother in one family and mildly retarded mother in the 2nd family. The anomalies of the 2 infants are not similar and are apparently unrelated to the 16p+ variant. Though the discovery of such euchromatic variants is highly significant for clinical diagnosis, their genetic significance and mode of origin remain to be elucidated.

Unusual mosaic trisomy 13 through 13/13 translocation and monosomy 13 with a small ring.

Apparently the first patient with de novo mosaicism 46,XX,t(13q13q)/46,XX,-13,+r(13) is described. The two cell lines were present at a frequency of 34% and 66%, respectively. The infant survived for about three months. The prominent dysmorphic features were: birth-weight and head circumference below the 3rd centile, encephalocele, multiple skin tags of low set dysplastic ears, coloboma of the left iris, short upward slanting palpebral fissures, and prominent nasal root. An imperforate anus, recto-vaginal fistula, enlarged adrenals, missing/hypoplastic kidneys, and limb anomalies were also present. It is postulated that the ring is a secondary anomaly arising from the 13q13q translocation.

Trisomy 22: no longer an enigma.

We describe a live-born male with 47,XY,+22. He had multiple congenital anomalies, severe growth retardation and psychomotor delay. Physical manifestations included broad nasal bridge, epicanthic folds, micrognathia, long philtrum, cleft palate, microcephaly with prominent occiput, apparently low-set malformed ears, heart murmur, genital anomaly, clinodactyly of the fifth fingers, and a low total finger ridge count. He died just before his 3rd birthday. Chromosome analysis by multiple banding techniques based on lymphocyte and fibroblast cultures confirm that the boy had complete trisomy 22.

Direct chromosome analysis from neonatal cord blood.

Direct chromosome preparations of neonatal cord blood provides the unique opportunity for rapid chromosome analysis (turnaround time; 6 hr), without the necessity of bone marrow aspiration. Based on 42 samples we confirm the finding of Garnham and Sutherland [1987] for suitability of cord blood for direct chromosome preparation. Procedural modifications are provided for higher yield of cells for chromosome analysis. The procedure may well be of major significance for rapid diagnosis of neonates who suffer from aneusomy.

Complete trisomy 17p a relatively new syndrome.

A patient with a de novo duplication of 17p is described. A comparison with five other published cases indicates several features in common that seem characteristic of the syndrome. Primary features include, low birth weight, small size, severe mental and motor retardation, heart defect, failure to thrive and peculiar facial traits. The prominent facial features are, a tendency for round and flat mid face, small palpebral fissures, hypertelorism, microcephaly and low set prominent ears.

Mosaic Down's syndrome with de novo 45,XX,-21,-22,+t(21q;22q)/46,XX,-21,+t(21q;21q) rearrangement.

The occurrence of mosaic Down's syndrome with two independent Robertsonian translocation cell lines is very rare. Such a patient is reported here, in whom an unbalanced Robertsonian translocation between two chromosomes 21 was detected in the majority of cells. The patient also revealed a minor cell line with a second Robertsonian translocation involving a chromosome 21 and a 22. The chromosome translocations detected in this patient were de novo in origin.

Tetraploidy: a report of three live-born infants.

We present three live-born infants with tetraploidy and compare them with two previously reported live-born infants with the same genetic defect. Common anomalies noted included microcephaly; a prominent, narrow forehead; microphthalmia/anophthalmia; cleft palate; orthopedic anomalies; genital ambiguity; and abnormalities of the central nervous system, including pituitary hypoplasia. Together these constitute a rather characteristic phenotype. An error in cytoplasmic cleavage is theorized to be a mechanism for the chromosome anomaly and is supported by the presence of parental polymorphisms in one of our cases; however, the presence of a small percentage of tetraploid cells in the leukocytes and skin fibroblasts of this patient's mother does not exclude maternal mosaicism as the basis for polyploidy in certain instances.