Damina Balmer

Terminal deletion, del(1)(p36.3), detected through screening for terminal deletions in patients with unclassified malformation syndromes.

We report on a 4 year-old girl with a 1p36.3-pter deletion. Clinical findings included minor anomalies of face and distal limbs, patent ductus arteriosus, the Ebstein heart anomaly, and brain atrophy with seizures. Conventional GTG-banded chromosome analysis revealed a normal (46,XX) result. Subsequent analysis by fluorescent in situ hybridization (FISH) using distal probes demonstrated a deletion of 1p36.6-pter. Molecular investigations with microsatellite markers showed hemizygosity at three loci at 1p36.3 with loss of the paternal allele. The deletion of 1p36.3 is difficult to identify by banding alone; indeed, our patient represents the third reported case with a del(1)(p36.3) that was detected only after more detailed analysis. In all three cases the deletion was detected through screening of patients with multiple congenital anomalies/mental retardation syndromes suggestive of autosomal chromosome aberrations for subtelomeric submicroscopic deletions by means of FISH or microsatellite marker analysis. On the basis of these observations we highly recommend that FISH with a subtelomeric 1p probe be routinely performed in patients with similar facial phenotype, severe mental retardation and seizures, and a heart malformation, particularly the Ebstein anomaly.

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.

Isochromosomes 12p and 9p: parental origin and possible mechanisms of formation

In a recent study Bugge etal1 and Kotzot etal2 reported that isochromosomes 18p originate mainly from maternal meiosis II nondisjunction, followed by misdivision. In order to determine if there is a common mechanism for isochromosome formation, three cases with mosaicism for an additional isochromosome 12p and three cases with tetrasomy 9p were studied. Two probands with isochromosomes 12p and the three cases with isochromosome 9p showed 3 alleles (two different maternal alleles and one paternal allele) at several loci mapping to distal 12p and 9p, respectively. Maternal heterozygosity for distal markers was reduced to homozygosity for markers closer to the centromere in both i(12p) cases and in one i(9p) case. For one patient with isochromosome 12p, the maternal band was clearly stronger than the paternal one at some loci, but two distinct maternal alleles were never seen. For one foetus and the patient with tetrasomy 9p, distal markers showed maternal heterozygosity. All proximal markers were not informative in these two i(9p) cases. Our findings indicate common features in different autosomal isochromosomes: the origin of the isochromosomes analysed is predominantly maternal; and a common mechanism appears to underlie their formation, namely due to meiosis II nondisjunction followed by a rearrangements leading to duplication of the short and loss of the long arm.

Molecular and clinical correlation study of Williams‐Beuren syndrome: No evidence of molecular factors in the deletion region or imprinting affecting clinical outcome

Williams-Beuren syndrome (WBS) results from a deletion of 7q11.23 in 90-95% of all clinically typical cases. Clinical manifestation can be variable and therefore, deletion size, inherited elastin (ELN) and LIM kinase 1 (LIMK1) alleles, gender, and parental origin of deletion have been investigated for associations with clinical outcome. In an analysis of 85 confirmed deletion cases, no statistically significant associations were found after Bonferronis correction for multiple pairwise comparisons. Furthermore, the present data do not support presence of imprinted genes in the WBS common deletion despite a nonsignificant excess of maternal over paternal deletions. Maternal deletion cases were more likely to have a large head circumference in the present data. Also, pairwise comparisons between individual WBS clinical features have been conducted and revealed significant associations between (1) low birth weight and poor postnatal weight gain (<10th percentile at the time of examination) and (2) transient infantile hypercalcemia and a stellate iris pattern. The latter association could indicate a common underlying etiology.

Supernumerary marker chromosome (1) of paternal origin and maternal uniparental disomy 1 in a developmentally delayed child

Editor—At least 168 cases with a supernumerary marker chromosome (SMC) from all chromosomes not including chromosome 15 have been documented.1 Birth prevalence is estimated at 0.14 to 0.72 per 1000.2 Subjects with a SMC have a partial trisomy (duplication) and in some cases a partial tetrasomy (triplication) of the genetic material contained in the SMC. The risk of an abnormal phenotype associated with a randomly ascertained de novo SMC derived from acrocentric autosomes (excluding chromosome 15) is estimated to be approximately 7% compared with approximately 28% for SMCs derived from non-acrocentric autosomes.1 The great variability of clinical findings in patients with SMCs originating from the same chromosome is probably the result of variation in size and genetic content, the degree of mosaicism, and uniparental disomy of the normal homologues of the chromosome from which the SMC derived. Evidence that subjects with SMCs might have an increased risk for UPD of the structurally normal homologues of the SMCs has been reported by several authors. To the best of our knowledge the coexistence of SMCs with UPD has been described for chromosomes 6, 7, 15, 20, and X.3-7 Here, we describe a further patient with multiple congenital anomalies, developmental delay, and the unique finding of coexistence of SMC 1 mosaicism and maternal uniparental disomy 1. The female patient was born at term after an uneventful pregnancy. At her birth, her mother was 33 years old and her father was 47 years old. Birth weight was 2500 g and length 49 cm. At the age of 6 years, she was investigated because of mental retardation. Height (1.14 m) and weight (17 kg) were within the normal range, but head circumference (44 cm) was far below the 3rd centile. Additional findings were temporal narrowing, downward slanting palpebral fissures, …

Severe intra-uterine growth retardation in a patient with maternal uniparental disomy 22 and a 22-trisomic placenta.

We report on a maternal uniparental disomy of chromosome 22 in a patient with severe intra‐uterine growth retardation. Karyotyping of a placental tissue revealed non‐mosaic trisomy 22, whereas lymphocyte chromosomes from the newborn were normal 46,XY. Microsatellite analysis using DNA extracted from white blood cells showed maternal uniparental heterodisomy for chromosome 22. Thus, the conceptus started as maternal trisomy due to meiotic non‐disjunction, and trisomy rescue occurred subsequently through loss of the paternal homologue resulting in maternal uniparental disomy. Normal phenotypes in previous reports have suggested that maternal UPD 22 has no impact on the phenotype. Thus, growth retardation in this patient was probably caused by dysfunction of the trisomic placenta. Copyright

Screening for UBE3A gene mutations in a group of Angelman syndrome patients selected according to non-stringent clinical criteria

Abstract. The Angelman syndrome (AS) is caused by genetic abnormalities affecting the maternal copy of chromosome region 15q12. Until recently, the molecular diagnosis of AS relied on the detection of either a deletion at 15q11–13, a paternal uniparental disomy (UPD) for chromosome 15 or imprinting mutations. A fourth class of genetic defects underlying AS was recently described and consists of mutations of the UBE3A gene. The vast majority of mutations reported so far are predicted to cause major disruptions at the protein level. It is unclear whether mutations with less drastic consequences for the gene product could lead to milder forms of AS. We report on our results obtained by screening 101 clinically diagnosed AS patients for mutations in the UBE3A gene. Non-stringent clinical criteria were purposely applied for inclusion of AS patients in this study. The mutation search was carried out by single-strand conformation polymorphism (SSCP), and SSCP/restriction fragment length polymorphism (RFLP) analyses and revealed five novel UBE3A gene mutations as well as three different polymorphisms. All five mutations were detected in patients with typical features of AS and are predicted to cause frameshifts in four cases and the substitution of a highly conserved residue in the fifth. The results we obtained add to the as yet limited number of reports concerning UBE3A gene mutations. Important aspects that emerge from the data available to date is that the four classes of genetic defects known to underlie AS do not appear to cover all cases. The genetic defect underlying approximately 10% of AS cases, including some familial cases, remains unknown.

A Novel Locus (DFNA24) for Prelingual Nonprogressive Autosomal Dominant Nonsyndromic Hearing Loss Maps to 4q35-qter in a Large Swiss German Kindred

Nonsyndromic hearing loss is one of the most genetically heterogeneous traits known. A total of 30 autosomal dominant nonsyndromic hearing-loss loci have been mapped, and 11 genes have been isolated. In the majority of cases, autosomal dominant nonsyndromic hearing loss is postlingual and progressive, with the exception of hearing impairment in families in which the impairment is linked to DFNA3, DFNA8/12, and DFNA24, the novel locus described in this report. DFNA24 was identified in a large Swiss German kindred with a history of autosomal dominant hearing loss that dates back to the middle of the 19th century. The hearing-impaired individuals in this kindred have prelingual, nonprogressive, bilateral sensorineural hearing loss affecting mainly mid and high frequencies. The DFNA24 locus maps to 4q35-qter. A maximum multipoint LOD score of 11.6 was obtained at 208.1 cM at marker D4S1652. The 3.0-unit support interval for the map position of this locus ranges from 205.8 cM to 211.7 cM (5.9 cM).

A supernumerary marker chromosome originating from two different regions of chromosome 18

By random amplification of a microdissected chromosome using the degenerate oligonucleotide primed polymerase chain reaction (DOP-PCR) and forward painting (microFISH), we characterised an extra structurally abnormal chromosome (ESAC) or supernumerary marker chromosome in a mentally retarded girl with a pattern of dysmorphic features. It could be clearly shown that the small marker chromosome originates from two different regions of chromosome 18, 18p11.1→18q11.1 and 18q12.3→18q21.1 respectively. Maternal origin of the de novo ESAC and biparental origin of the normal homologues of chromosome 18 were shown by PCR of several highly polymorphic microsatellites. In this case, application of microFISH was a prerequisite for rapid and precise characterisation of an ESAC. A definite identification of this discontinuous supernumerary marker chromosome would not have been possible using FISH with centromere specific probes or multicolour FISH approaches.

Duplication of segment 1p21 following paternal insertional translocation, ins(6;1)(q25;p13.3p22.1).

A moderately mentally retarded 3 year old boy showed minor anomalies including a prominent forehead and flat occiput, exophthalmos, large and prominent ears, high arched palate, umbilical hernia, sacral dimple, and irregular position of the toes. Cardiac sonography disclosed a chorda running through the left ventricle. Cytogenetic investigation of the family showed a balanced insertional translocation of segment 1p13→p22 into distal 6q in the father which had led, through unbalanced segregation, to duplication of 1p13.3→p22.1 in the proband. Familial duplication of such a small interstitial segment of 1p has not been reported previously, and the paucity of abnormal physical findings in the proband compared to previous patients with a similar aberration is remarkable.