Angela Schmidt

The centromeric 11p15 imprinting centre is also involved in Silver–Russell syndrome

Silver–Russell syndrome (SRS) is a heterogeneous disorder characterised by severe intrauterine and postnatal growth retardation, limb and body asymmetry, a typical facial appearance and less common dysmorphisms. Recently, epimutations and maternal duplications affecting the short arm of chromosome 11 have been shown to have a crucial role in the aetiology of the disease. Disturbances in the same genomic region cause the overgrowth disorder Beckwith–Wiedemann syndrome (BWS). In BWS, mutations in the telomeric as well as in the centromeric imprinting centres (ICR1 and ICR2) in 11p15 can be observed. In SRS, methylation defects in the imprinted region in 11p15 were considered to be restricted to the telomeric ICR1. They can be detected in about 30% of patients. This article reports on the first patient with SRS with a cryptic duplication restricted to the centromeric ICR2 domain in 11p15. The maternally inherited duplication in this patient included a region of 0.76–1 Mbp and affected the genes regulated by the ICR2, among them CDKN1C and LIT1. This study provides evidence for a role for this imprinting centre in the aetiology of SRS and shows that SRS presents a picture genetically opposite to that of BWS.

Fragile site Xq27 and mental retardation. Clinical and cytogenetic manifestation in heterozygotes and hemizygotes of five kindreds.

SummaryClinical and cytogenetic data of five kindreds with X-linked mental retardation and a methotrexate-inducible fragile site at the distal long arm of the X chromosome fra(X)(q27) are reported; comprising a total of 26 individuals studied cytogenetically, 10 hemizygotes, five obligate heterozygotes, seven facultative heterozygotes, and four normal males, i.e., fathers and brothers of affected hemizygotes. The heterozygotes in two of these sibships show partial phenotypic and/or mental manifestation. Two of them, who are obligate heterozygotes, expressed fra(X)(q27) in 23% and 16% of their metaphases at the ages of 27 and 53 years. In the obligate and facultative heterozygotes, who are mentally normal, the marker X chromosome could not be detected in lymphocyte cultures. We conclude from these findings that the occurrence of fra(X)(q27) might correlate with the phenotypic expression in heterozygotes rather than with the age of the individual.

Prenatal detection of a fetus hemizygous for the fragile X-chromosome

SummaryA male fetus of a pregnancy known to be at risk for X-linked mental retardation with fragile site Xq27 was found to be affected by demonstrating the marker X-chromosome in five of 180 (2.8%) of metaphases derived from amniocytes cultured in medium 199. The results were confirmed in fetal lymphocytes (25 of 86 metaphases, i.e. 29%), and fetal fibroblasts (five of 100 metaphases when cultured in medium 199, and 14 of 100 after exposure to methotrexate for 43 h).

New Immortalized Cell Lines of Patients With Small Supernumerary Marker Chromosome Towards the Establishment of a Cell Bank

Sixteen newly established cell lines with small supernumerary marker chromosomes (sSMC) derived from chromosomes 1, 2, 4, 6, 7, 8, 14, 15, 16, 18, 19, 21, and 22 are reported. Two sSMC are neocentric and derived from 15q24.1-qter and 2q35-q36, respectively. Two further cases each present with two sSMC of different chromosomal origin. sSMC were characterized by multicolor fluorescence in situ hybridization for their chromosomal origin and genetic content. Moreover, uniparental disomy of the sister chromosomes of the sSMC was excluded in all nine cases studied for that reason. The 16 cases provide information to establish a refined genotype-phenotype correlation of sSMC and are available for future studies.

A supernumerary marker chromosome with a neocentromere derived from 5p14→pter

Editor—Supernumerary marker chromosomes (SMCs) comprise a heterogeneous group of structurally arranged chromosomes. SMCs are found in approximately 0.14-0.72/1000 newborns1-3 and they may be associated with developmental abnormalities and malformations.4 The great variability of clinical symptoms in patients with SMCs is the result of the difference in the genetic content of the marker. The phenotypic consequences of SMCs are difficult to predict, especially if a de novo marker is detected prenatally. Therefore, the precise identification of a marker chromosome is of essential importance in genetic counselling. Earlier figures based on the results of a large prenatal multicentre study using conventional methods suggested a risk for an abnormal phenotype of 13% for SMCs.5 Combining FISH data and conventional analyses, the estimated risk for an abnormal phenotype turned out to be twice as high, approximately 28% for non-acrocentric autosomal SMCs and about 7% for acrocentric autosomal SMCs.6 An even more accurate method of identification of the chromosomal origin of supernumerary marker chromosomes is FISH with microdissection probes and reverse painting, allowing a definite delineation of phenotype-karyotype correlations.7 In recent years, a novel class of mitotically stable human marker chromosomes that are devoid of alpha satellite DNA has been identified.8 9 These analphoid markers have been shown to contain functional centromeres outside the normal centromere domain, which are called neocentromeres. Marker chromosomes derived from chromosome 5 are rare and a marker chromosome 5 with a neocentromere has not been reported so far. We describe a patient with an inverted duplication of the distal part of the short arm of chromosome 5 and the formation of a neocentromere leading to a supernumerary marker chromosome. The comparison of the clinical findings of this patient with a tetrasomy of distal 5p with similar cases previously described suggests a gene …

Unilateral split hand in one of monozygotic twins

SummaryAtypical split hand (left) was observed in one of monozygotic twins. The probability for monozygosity was 0.997 as based on 18 autosomal loci (11 blood groups and 7 enzymes and serum proteins). This observation supports the thesis that atypical split hand is not genetically determined and must be distinguished from autosomal dominant ectrodactyly.

The phenotype in de novo and familial pericentric inversion 6. A problem in karyotype-phenotype correlation

SummaryA 15-month-old girl with a de novo pericentric inversion 6(p12q15) is described. No chromosomal imbalance could be detected, but multiple dysmorphic features such as low birth weight, short stature, mental retardation, macrocephaly, hypertelorism, broad and impressed nasal bridge, seizures, and delayed developmental milestones suggest the possibility of an unrecognized chromosomal imbalance, although a fortuitous association is also possible. The HLA region was not involved.

Sporadic translocation, inversion, and marker chromosome in prenatal diagnosis

We have observed a de novo pericentric inversion 6 [inv(6)(pter-, p12::q15~p12::q15~qter)] in lymphocyte and fibroblasts cultures of a 15-month-old girl with multiple dysmorphic features, such as low birth weight, short stature, decreased bone age, mental retardation, delayed motor and speech development, macrocephaly, hypertelorism, broad and impressed nasal bridge, and seizures. There seemed to be no chromosomal imbalance and we wonder whether the clinical findings are coincidental or not. We would like to compare data on similar observations.

Multiple Y-chromosomal aberrations in a patient with mixed gonadal dysgenesis of XO/XY Type

We have observed a de novo pericentric inversion 6 [inv(6)(pter-, p12::q15~p12::q15~qter)] in lymphocyte and fibroblasts cultures of a 15-month-old girl with multiple dysmorphic features, such as low birth weight, short stature, decreased bone age, mental retardation, delayed motor and speech development, macrocephaly, hypertelorism, broad and impressed nasal bridge, and seizures. There seemed to be no chromosomal imbalance and we wonder whether the clinical findings are coincidental or not. We would like to compare data on similar observations.

Phenotypic manifestation and pericentric inversion 6

We have observed a de novo pericentric inversion 6 [inv(6)(pter-, p12::q15~p12::q15~qter)] in lymphocyte and fibroblasts cultures of a 15-month-old girl with multiple dysmorphic features, such as low birth weight, short stature, decreased bone age, mental retardation, delayed motor and speech development, macrocephaly, hypertelorism, broad and impressed nasal bridge, and seizures. There seemed to be no chromosomal imbalance and we wonder whether the clinical findings are coincidental or not. We would like to compare data on similar observations.