Increased parental ages and uniparental disomy 15: a paternal age effect?

Parental ages associated with both maternal and paternal uniparental disomy (UPD) of chromosome 15 are highly elevated in comparison to Zurich population-based controls, with mean maternal and paternal ages of 35.6 and 38.1, respectively for UPD patients (diagnosed in Zurich) and 28.

Clinical and molecular analysis of five inv dup(15) patients.

Five patients with inv dup(15) chromosomes were investigated with molecular probes on proximal 15q to determine the parental origin and extent of the duplicated segment. Cytogenetic investigation showed that four patients carried one and a fifth patient had two extra chromosomes derived from number 15 in all cells. In situ hybridization with a chromosome 15 library and a centromere 15 probe confirmed that the entire inv dup chromosomes were derived from chromosome 15.

Small nuclear ribonucleoprotein polypeptide N (SNRPN), an expressed gene in the Prader-Willi syndrome critical region.

Prader-Willi syndrome (PWS) is associated with paternally derived chromosomal deletions in region 15q11-13 or with maternal disomy for chromosome 15. Therefore, loss of the expressed paternal alleles of maternally imprinted genes must be responsible for the PWS phenotype. We have mapped the gene encoding the small nuclear RNA associated polypeptide SmN (SNRPN) to human chromosome 15q12 and a processed pseudogene SNRPNP1 to chromosome region 6pter-p21.

DNA polymorphism analysis in families with recurrence of free trisomy 21.

We used DNA polymorphic markers on the long arm of human chromosome 21 in order to determine the parental and meiotic origin of the extra chromosome 21 in families with recurrent free trisomy 21. A total of 22 families were studied, 13 in which the individuals with trisomy 21 were siblings (category 1), four families in which the individuals with trisomy 21 were second-degree relatives (category 2), and five families in which the individuals with trisomy 21 were third-degree relatives, that is, their parents were siblings (category 3). In five category 1 families, parental mosaicism was detected, while in the remaining eight families, the origin of nondisjunction was maternal.

[Molecular genetics diagnosis of Steinert's myotonic dystrophy].

Myotonic dystrophy (DM) is the most common neuromuscular disease with adult onset (incidence 1 in 8000). The biochemical basis of this autosomal dominantly inherited disease is still unknown. The most striking features are myotonia and progressive muscular wasting.

The acrocallosal syndrome and Greig syndrome are not allelic disorders.

Acrocallosal syndrome is an autosomal recessive form of polysyndactyly associated with mental retardation and agenesis of the corpus callosum. There have been suggestions that it is allelic to the Greig cephalopolysyndactyly syndrome. Linkage analysis, using flanking markers, shows this suggestion is unlikely to be correct.

Linkage of Rieger syndrome to the region of the epidermal growth factor gene on chromosome 4.

Rieger syndrome is an autosomal dominant disorder of morphogenesis in which previous cytogenetic arrangements have suggested chromosome 4 as a candidate chromosome. Using a group of highly polymorphic short tandem repeat polymorphisms (STRP), including a new tetranucleotide repeat for epidermal growth factor (EGF), significant linkage of Rieger syndrome to 4q markers has been identified. Tight linkage to EGF supports its role as a candidate gene, although a recombinant in an unaffected individual has been identified.

Reduced recombination and paternal age effect in Klinefelter syndrome.

The parental origin of the additional sex chromosome was studied in 47 cases with an XXY sex chromosome constitution. In 23 cases (49%), the error occurred during the first paternal meiotic division. Maternal origin of the additional chromosome was found in the remaining 24 cases (51%).

Brain stem and cervical cord dysraphic lesions in iniencephaly.

Iniencephaly is a rare, lethal, axial dysraphic malformation complex diagnosed on the basis of three cardinal features: deficiency of the occipital bone, cervicothoracic spinal retroflexion, and rachischisis. The majority of the patients also have various associated viscerae malformations. An iniencephalic female fetus delivered at 35 5/7 weeks of gestation revealed severe anomalies of the central nervous system and the spine: the cerebellar vermis was hypoplastic, the medulla oblongata was flattened and broadened, and the cervical canal was widely patent dorsally.

Confirmation and refinement of the genetic localization of the Coffin-Lowry syndrome locus in Xp22.1-p22.2.

The Coffin-Lowry syndrome (CLS) is an X-linked inherited disease of unknown pathogenesis characterized by severe mental retardation, typical facial and digital anomalies, and progressive skeletal deformations. Our previous linkage analysis, based on four pedigrees with the disease, suggested a localization for the CLS locus in Xp22.1-p22.

The genes for the highly homologous Ca(2+)-binding proteins oncomodulin and parvalbumin are not linked in the human genome.

The chromosomal loci of the human parvalbumin and oncomodulin single-copy genes that encode structurally and evolutionarily closely related Ca(2+)-binding proteins were determined by somatic cell hybrid analysis. Southern blot analysis of genomic DNA from 25 human-hamster somatic cell hybrids showed that the human gene for oncomodulin resides on chromosome 7. Analysis of human-mouse hybrids selectively retaining human chromosome 7 or a portion of it allowed specific assignment of the gene locus to the p11-p13 region of chromosome 7 known to be mutated or deleted in patients with the Greig cephalopolysyndactyly syndrome.

The meiotic stage of nondisjunction in trisomy 21: determination by using DNA polymorphisms.

We have studied DNA polymorphisms at loci in the pericentromeric region on the long arm of chromosome 21 in 200 families with trisomy 21, in order to determine the meiotic origin of nondisjunction. Maintenance of heterozygosity for parental markers in the individual with trisomy 21 was interpreted as resulting from a meiosis I error, while reduction to homozygosity was attributed to a meiosis II error. Nondisjunction was paternal in 9 cases and was maternal in 188 cases, as reported earlier.

Molecular study of 45,X conceptuses: correlation with clinical findings.

The parental origin of the single X in 45 cases (40 liveborns and 5 fetuses) with a 45,X karyotype was studied using polymorphic DNA probes. The single X was paternal in origin (Xp) in 10 cases (22.2%) and maternal (Xm) in 35 cases (77.

No evidence for a paternal interchromosomal effect from analysis of the origin of nondisjunction in Down syndrome patients with concomitant familial chromosome rearrangements.

The parental origin of the extra chromosome 21 was determined with DNA polymorphisms in seven families in whom the proband and one of the parents carried an additional chromosome rearrangement (balanced translocation or pericentric inversion) not involving chromosome 21. The balanced rearrangement was inherited from the mother in two families and from the father in five families, whereas the additional chromosome 21 was derived from the mother in all seven families. These findings are not in agreement with the hypothesis of a paternal interchromosomal effect.

Clinical and ERG data in a family with autosomal dominant RP and Pro-347-Arg mutation in the rhodopsin gene.

In a family with autosomal dominant retinitis pigmentosa, documented over six generations, a previously undescribed point mutation in the rhodopsin gene could be identified. The mutation found in the six affected members examined but in none of the controls, including healthy members of the family, was a point mutation in codon 347 predicting a substitution of the amino acid arginine for proline, designated Pro-347-Arg. Six affected members from two generations were examined clinically and with ganzfeld rod and cone electroretinography.

Uniparental origin of sex chromosome polysomies.

The parental origin of the additional sex chromosomes in 8 cases with high-order sex chromosome polysomies was determined using DNA polymorphisms. The additional sex chromosomes were paternally derived in 3 48,XXYY cases, and maternal in origin in 1 48,XXXY case and 4 49,XXXXY cases. Thus, all extra chromosomes, within a particular patient, were always derived from only one parent.

Expression of the fragile-X in the "premutated"/"non-imprinted" state.

Data about the expression of the fragile site at Xq27.3 from 74 daughters of normal transmitting males (NTMs) were collected from 7 different genetic centers. The majority (85.

Molecular, cytogenetic, and clinical investigations of Prader-Willi syndrome patients.

Thirty-seven patients presenting features of the Prader-Willi syndrome (PWS) have been examined using cytogenetic and molecular techniques. Clinical evaluation showed that 29 of these patients fulfilled diagnostic criteria for PWS. A deletion of the 15q11.

A molecular study of X isochromosomes: parental origin, centromeric structure, and mechanisms of formation.

Fourteen individuals with an i(Xq) or idic(Xq) were studied using RFLP analysis in order to determine both parental origin and extent of heterozygosity of the isochromosome and to search for the presence of short-arm material. In five cases the isochromosome was paternally derived, while nine patients had a maternal i(Xq). The analysis of heterozygosity of the nine maternally derived isochromosomes by using Xq markers showed heterozygosity in two cases, suggesting an origin from two homologous X chromosomes.

[Anal sphincter dysplasia as cause of chronic defecation disorders: a clinical and genetic study].

Anal sphincter dysplasia is a congenital, often familial malformation of the anal canal. In the literature, the anomaly is poorly represented and usually referred to as anteriorly or ventrally displaced anus. The range of symptoms includes chronic constipation, severe straining at defecation, encopresis and chronic paradoxical diarrhea with fecal incontinence.

A case of Hirschsprung disease with a chromosome 13 microdeletion, del(13)(q32.3q33.2): potential mapping of one disease locus.

A mentally retarded boy with discrete physical findings, Hirschsprung disease (HD) and a microdeletion of 13q,del(13)(q32.3q33.2) is described.

Pro-347-Arg mutation of the rhodopsin gene in autosomal dominant retinitis pigmentosa.

It has been shown recently that autosomal dominant retinitis pigmentosa may be caused by point mutations of the rhodopsin gene in a portion of families. In this communication, a large six-generation family with autosomal dominant RP is described. Molecular analysis by PCR amplification followed by restriction digestion or heteroduplex analysis suggested a point mutation in codon 347, in which two different mutations (Pro-347-Ser and Pro-347-Leu) have already been reported.

Down syndrome due to de novo Robertsonian translocation t(14q;21q): DNA polymorphism analysis suggests that the origin of the extra 21q is maternal.

Down syndrome is rarely due to a de novo Robertsonian translocation t(14q;21q). DNA polymorphisms in eight families with Down syndrome due to de novo t(14q;21q) demonstrated maternal origin of the extra chromosome 21q in all cases. In seven nonmosaic cases the DNA markers showed crossing-over between two maternal chromosomes 21, and in one mosaic case no crossing-over was observed (this case was probably due to an early postzygotic nondisjunction).