A recoding scheme for X-linked and pseudoautosomal loci to be used with computer programs for autosomal LOD-score analysis

We present a recoding scheme that allows for a parametric multipoint X-chromosomal linkage analysis of dichotomous traits in the context of a computer program for autosomes that can use trait models with imprinting. Furthermore, with this scheme, it is possible to perform a joint multipoint analysis of X-linked and pseudoautosomal loci. It is required that (1) the marker genotypes of all female nonfounders are available and that (2) there are no male nonfounders who have daughters in the pedigree. The second requirement does not apply if the trait locus is pseudoautosomal. The X-linked marker loci are recorded by adding a dummy allele to the males' hemizygous genotypes. For modelling an X-linked trait locus, five different liability classes are defined, in conjunction with a paternal imprinting model for male nonfounders. The formulation aims at the mapping of a diallelic trait locus relative to an arbitrary number of codominant markers with known genetic distances, in cases where a program for a genuine X-chromosomal analysis is not available.     

X-linked ocular albinism

Summary A pedigree of X-linked ocular albinism is presented containing nine affected males and 10 heterozygous females. One carrier female showed ocular changes similar to those of affected males. She is considered to be a manifesting heterozygote, a situation explained by the Lyon hypothesis. One affected male married a female with autosomal recessive ocular albinism and produced one daugher with the fundus changes of the carrier state of X-linked ocular albinism, and one son with normal eyes. The daughter did not show any evidence of the additive effect of the two different genes for X-linked and autosomal recessive ocular albinism.     

A mutation in the rett syndrome gene, MECP2, causes X-linked mental retardation and progressive spasticity in males

Heterozygous mutations in the X-linked MECP2 gene cause Rett syndrome, a severe neurodevelopmental disorder of young females. Only one male presenting an MECP2 mutation has been reported; he survived only to age 1 year, suggesting that mutations in MECP2 are male lethal. Here we report a three-generation family in which two affected males showed severe mental retardation and progressive spasticity, previously mapped in Xq27.2-qter. Two obligate carrier females showed either normal or borderline intelligence, simulating an X-linked recessive trait. The two males and the two obligate carrier females presented a mutation in the MECP2 gene, demonstrating that, in males, MECP2 can be responsible for severe mental retardation associated with neurological disorders.     

Multiple malformations in a male and maternal osteopathia strata with cranial sclerosis (OSCS)

Osteopathia striata with cranial sclerosis (OSCS), conductive hearing impairment and a characteristic facial appearance is the clinical manifestation in carrier women of an X-linked disease. We report on a family with typical OSCS in the mother, a maternal aunt and the grandmother, and multiple severe malformations in the son. He was affected by cranial sclerosis with frontal bossing, conductive hearing impairment, cleft palate, thoracic dysplasia, mesenterium commune with non-rotation of the gut, anal atresia, bilateral cutaneous syndactyly of 3rd and 4th fingers, duplication of the distal phalanx of 2nd and 3rd fingers on the right, bilateral fibular aplasia with clubfeet, developmental retardation, epileptic seizures, hypothyroidism, and hypertrophic pyloric stenosis. The X-inactivation pattern in peripheral leucocytes of one informative carrier woman was random. Our case and several literature reports confirm that males which are hemizygous for the OSCS trait suffer from a dysmorphic syndrome with characteristic multiple malformations as a distinct entity. There is, at present, no reason to assume genetic heterogeneity with an autosomal dominant OSCS variant.     

Remapping of the RP15 locus for X-linked cone-rod degeneration to Xp11.4-p21.1, and identification of a de novo insertion in the RPGR exon ORF15

X-linked forms of retinitis pigmentosa (XLRP) are among the most severe, because of their early onset, often leading to significant vision loss before the 4th decade. Previously, the RP15 locus was assigned to Xp22, by linkage analysis of a single pedigree with "X-linked dominant cone-rod degeneration." After clinical reevaluation of a female in this pedigree identified her as affected, we remapped the disease to a 19.5-cM interval (DXS1219-DXS993) at Xp11.4-p21.1. This new interval overlapped both RP3 (RPGR) and COD1. Sequencing of the previously published exons of RPGR revealed no mutations, but a de novo insertion was detected in the new RPGR exon, ORF15. The identification of an RPGR mutation in a family with a severe form of cone and rod degeneration suggests that RPGR mutations may encompass a broader phenotypic spectrum than has previously been recognized in "typical" retinitis pigmentosa.     

Estimation of male to female ratio of mutation rates from carrier-detection tests in X-linked disorders.

A method is presented for the estimation of the ratio of male to female mutation rates from female carrier-detection test data from pedigrees containing an isolated male manifesting an X-linked necessive disorder. Pedigrees of any size and complexity (barring consanguinity) and containing any number of tested females can be utilized. The relative fitness of affected males and carrier females, and the segregation probability of the abnormal gamete in females, can be estimated simultaneously with the ratio of mutation rates in order to test specific hypotheses against given bodies of data. Here this method is applied to families containing isolated individuals affected with Lesch-Nyhan syndrome.     

Two models for a maternal factor in the inheritance of Huntington disease

Huntington disease is a classic example of an autosomal dominant trait. Over the years, however, a number of investigators have reported anomalies regarding the age of onset of the disease that are inconsistent with this paradigm. We propose two models in which a maternal factor--cytoplasmic in one case, autosomal or X-linked in the other--acts to delay onset in a manner consistent with the previously reported anomalies. Relevant data from the Huntington's Disease Research Roster are presented that reinforce and extend the previous observations.     

A dog possessing high glutathione (GSH) and K concentrations with an increased Na, K-ATPase activity in its erythrocytes

We have studied a female mongrel dog found in Kanagawa Prefecture, Japan. This dog was selected and examined thoroughly because she naturally maintained a high glutathione (GSH) concentration in her erythrocytes and did not exhibit any clinical signs or hematologic disorders. Erythrocytes from this animal demonstrated high K and low Na concentrations, as well as accumulation of the amino acids, glutamic acid, aspartic acid and glutamine. The Na, K-ATPase activity was also markedly elevated and the osmotic fragility of the dog's erythrocytes was found to be significantly increased. Crossbreeding of our dog with a normal dog and also with a heterozygous carrier dog revealed that the genetic abnormality possessed by our dog is transmitted as an autosomal recessive trait. All of the clinical data obtained from studying this animal strongly suggest that it possesses a genetic trait similar to that of the HK dogs previously described by Maede.     

The mode of genetic transmission of a gouty family with increased phosphoribosylpyrophosphate synthetase activity

Summary The mode of genetic transmission of gout and increased activity of phosphoribosylpyrophosphate synthetase (PRPPS) was studied in one family. Among 15 members of Family F, two male members had gout and had PRPPS activity of erythrocyte lysates three times higher than normal subjects. Five female members had activity 2.5 times higher than normal. The difference between the activities of male and female affected members was statistically significant (P<0.05). To examine the genetic trait of this abnormal PRPPS, the incorporation of ³H-adenine into erythrocytes or lymphocytes was studied using autoradiography. The number of grains which show the uptake of labeled adenine into cells revealed a normal distribution pattern in two normal persons and in two male patients, and a mixed pattern of the two cell populations in two female affected members. These results suggested mosaicism in female members and X-linked dominant transmission of this trait. Thermal inactivation of PRPPS of an affected female was intermediate between that from a normal subject and that from the affected males. This result showed the heterogeneity of the PRPPS from the hemolysate of an affected famale. The genotype of PRPPS on the X-chromosome was assumed and the lod score between PRPPS and Xg was also estimated. From these findings and electrophoretical study, it was suggested that the abnormal enzyme was a mutant enzyme transmitted in an X-linked dominant trait, and that the mutation occurred on the structural gene of the PRPPS.     

Canine X-linked muscular dystrophy in Japan (CXMDJ).

The purpose of this study was to develop a strain of canine X-linked muscular dystrophy (CXMD), a model of Duchenne muscular dystrophy, in Japan. A female beagle was artificially inseminated with frozen-thawed spermatozoa derived from an affected golden retriever. Subsequently, two carrier female dogs (G1 carriers) and four normal male littermates were produced. Thereafter, the two G1 carriers were mated with beagle sires. As a result, each bitch whelped three times, and out of 54 pups, 17 affected male descendants, and 11 carrier female descendants (G2 carriers) were detected. One G2 carrier was then mated with a beagle sire and 15 pups in two whelpings were produced, including five affected males and four carrier females (G3 carriers). A total of 10 female beagles were artificially inseminated to evaluate the fertility of the frozen-thawed spermatozoa from the two affected dogs. The whelping rates of the two affected dogs were 4/5 and the litter sizes were 5.0 +/- 1.41 and 6.0 +/- 0.82, respectively. These results indicate that a canine X-linked muscular dystrophy colony has been established in Japan. We called them CXMDJ.     

X-linked dominant cone-rod degeneration: linkage mapping of a new locus for retinitis pigmentosa (RP 15) to Xp22.13-p22.11.

Retinitis pigmentosa is the name given to a heterogeneous group of hereditary retinal degenerations characterized by progressive visual field loss, pigmentary changes of the retina, abnormal electroretinograms, and, frequently, night blindness. In this study, we investigated a family with dominant cone-rod degeneration, a variant form of retinitis pigmentosa. We used microsatellite markers to test for linkage to the disease locus and excluded all mapped autosomal loci. However, a marker from the short arm of the X chromosome, DXS989, showed 0% recombination to the disease locus, with a maximum lod (log-odds) score of 3.3. On the basis of this marker, the odds favoring X-linked dominant versus autosomal dominant inheritance are > 10(5):1. Haplotype analysis using an additional nine microsatellite markers places the disease locus in the Xp22.13-p22.11 region and excludes other X-linked disease loci causing retinal degeneration. The clinical expression of the retinal degeneration is consistent with X-linked dominant inheritance with milder, variable effects of Lyonization affecting expression in females. On the basis of these data we propose that this family has a novel form of dominant, X-linked cone-rod degeneration with the gene symbol "RP15."     

The expanding phenotypic spectrum of female <Emphasis Type="Italic">SLC9A6</Emphasis> mutation carriers: a case series and review of the literature

Christianson syndrome (OMIM 300243), caused by mutations in the X-linked SLC9A6 gene, is characterized by severe global developmental delay and intellectual disability, developmental regression, epilepsy, microcephaly and impaired ocular movements. It shares many common features with Angelman syndrome. Carrier females have been described as having learning difficulties with mild to moderate intellectual disability, behavioural issues and psychiatric illnesses. There is little literature on the carrier female phenotype of Christianson syndrome. We describe a large extended family with three affected males, four carrier females, one presumed carrier female and one obligate carrier female with a c.190G>T, p.E64X mutation known to cause a premature stop codon in SLC9A6. We characterize and expand the clinical phenotype of female SLC9A6 mutation carriers by comparing our described family with female carriers previously discussed in the literature. In particular, we highlight the neurodevelopmental and psychiatric phenotypes observed in our family and previous reports.     

X chromosome influences sperm length in the stalk-eyed fly Cyrtodiopsis dalmanni

Whether sexually selected traits are sex linked can have profound effects on their evolution. In the diopsid stalk-eyed fly, Cyrtodiopsis dalmanni, sperm length and female reproductive tract morphology have coevolved across species, postcopulatory sexual selection is known to occur, and X-linked genes affect female ventral sperm receptacle size. Here, we estimate the location of quantitative trait loci (QTL) for spermatocyst tail length by using F2 progeny segregating for an X-linked factor that causes sex-ratio meiotic drive. We found two QTL, including a major X-linked QTL responsible for 25% of the variation in spermatocyst tail length 2.1 cM from the sex-ratio element and 0.8 cM from a major eye span QTL. Sex-ratio males produce shorter spermatocyst tails and shorter eye spans. Thus, X-linked factors affect both pre- and postcopulatory traits, and linkage between the alleles for short eye span and short spermatocyst tail length allow pre- and postcopulatory sexual selection to potentially act in concert against the transmission bias caused by the sex-ratio chromosome.     

Detection of New Paternal Dystrophin Gene Mutations in Isolated Cases of Dystrophinopathy in Females

Duchenne muscular dystrophy is one of the most common lethal monogenic disorders and is caused by dystrophin deficiency. The disease is transmitted as an X-linked recessive trait; however, recent biochemical and clinical studies have shown that many girls and women with a primary myopathy have an underlying dystrophinopathy, despite a negative family history for Duchenne dystrophy. These isolated female dystrophinopathy patients carried ambiguous diagnoses with presumed autosomal recessive inheritance (limbgirdle muscular dystrophy) prior to biochemical detection of dystrophin abnormalities in their muscle biopsy. It has been assumed that these female dystrophinopathy patients are heterozygous carriers who show preferential inactivation of the X chromosome harboring the normal dystrophin gene, although this has been shown for only a few X:autosome translocations and for two cases of discordant monozygotic twin female carriers. Here we study X-inactivation patterns of 13 female dystrophinopathy patients—10 isolated cases and 3 cases with a positive family history for Duchenne dystrophy in males. We show that all cases have skewed X-inactivation patterns in peripheral blood DNA. Of the nine isolated cases informative in our assay, eight showed inheritance of the dystrophin gene mutation from the paternal germ line. Only a single case showed maternal inheritance. The 10-fold higher incidence of paternal transmission of dystrophin gene mutations in these cases is at 30-fold variance with Bayesian predictions and gene mutation rates. Thus, our results suggest some mechanistic interaction between new dystrophin gene mutations, paternal inheritance, and skewed X inactivation. Our results provide both empirical risk data and a molecular diagnostic test method, which permit genetic counseling and prenatal diagnosis of this new category of patients.     

Gaucher's and Fabry's diseases: biochemical and genetic aspects

Gaucher and Fabry's diseases are lysosomal storage disorders. They are due to glucocerebrosidase or alpha galactosidase deficiency, respectively. Gaucher disease, transmitted as an autosomal recessive trait, is frequent among Ashkenazi Jews. Cloning of the gene has allowed the characterization of few common mutations. Some of them have a prognosis value, in favour of either a non neurological form (type 1) or more severe forms (types 2 and 3). There mutations were found in 70% of the alleles, the other alleles carrying private mutations. Fabry disease is transmitted as an X-linked recessive trait. Genetic counselling in at-risk families relies on the detection of carrier females. As the alpha galactosidase gene shows various mutations, the establishment of phenotype-genotype correlations is limited. These two diseases, well defined at the biochemical and genetic level, are good models of inherited diseases for the development of specific therapies.     

Prenatal diagnosis of X-linked choroideremia with mental retardation,associated with a cytologically detectable X-chromosome deletion

Summary We describe a family in which an X-chromosome deletion is segregating with choroideremia, an X-linked recessive condition. The DNA sequences DXYS1 and DXS3, defined by the probes pDP34 and 19.2 respectively, are absent in the affected male (who is also mentally retarded), and hemizygous in his mother and in his carrier sister, who presented early in pregnancy. Analysis of chorionic villus DNA formed the basis of prenatal exclusion of choroideremia in her male fetus. In three female relatives, studied with late-labelling techniques, the deleted X was preferentially inactivated in 86–100% of cells studied. This family confirms the localisation of the choroideremia locus to within Xq1321, and places the loci for anhidrotic ectodermal dysplasia and the X-linked immunodeficiencies outside this region.     

Single cell co-amplification of polymorphic markers for the indirect preimplantation genetic diagnosis of hemophilia A,X-linked adrenoleukodystrophy,X-linked hydrocephalus and incontinentia pigmenti loci on Xq28

Preimplantation genetic diagnosis (PGD) first consisted of the selection of female embryos for patients at risk of transmitting X-linked recessive diseases. Advances in molecular biology now allow the specific diagnosis of almost any Mendelian disease. For families with an identified X-linked recessive disease-causing mutation, non-specific diagnosis by sex identification can be considered as a sub-standard method, since it involves the unnecessary disposal of healthy male embryos and reduces success rate by diminishing the pool of embryos eligible for transfer. The most telomeric part of the X-chromosome long arm is a highly gene-rich region encompassing disease genes such as haemophilia A, X-linked adrenoleukodystrophy, X-linked hydrocephalus and incontinentia pigmenti. We developed five single-cell triplex amplification protocols with microsatellite markers DXS1073, DXS9901 (BGN), G6PD, DXS1108, DXS8087 and F8C-IVS13 located in this Xq terminal region. These tests allow the diagnosis of all diseases previously mentioned providing that the genetic material allowing the identification of the morbid allele can be obtained. The choice of the microsatellite set to use depends on the localisation of the gene responsible for the diagnosed pathology and on the informativity of the markers in particular families. Single-cell amplification efficiency was assessed on single lymphocytes. Amplification rate of the different markers ranged from 89–97% with an allele drop out rate of 2–19 %. So far PGD has been carried out for three carrier females at risk of transmitting X-linked adrenoleukodystrophy, X-linked hydrocephalus and hemophilia A. The latter one is now pregnant.     

A mutation in the pleckstrin homology (PH) domain of the FGD1 gene in an Italian family with faciogenital dysplasia (Aarskog-Scott syndrome)

Aarskog-Scott Syndrome (AAS) is an X-linked disorder characterised by short stature and multiple facial, limb and genital abnormalities. A gene, FGD1, altered in a patient with AAS phenotype, has been identified and found to encode a protein with homology to Rho/Rac guanine nucleotide exchange factors (Rho/Rac GEF). However, since this original report on identification of a mutated FGD1 gene in an AAS patient, no additional mutations in the FGD1 gene have been described. We analysed 13 independent patients with clinical diagnosis of AAS. One patient presented a mutation that results in a nucleotide change in exon 10 of the FGD1 gene (G2559>A) substituting a Gln for Arg in position 610. The mutation was found to segregate with the AAS phenotype in affected males and carrier females in the family of this patient. Interestingly, Arg-610 is located within one of the two pleckstrin homology (PH) domains of the FGD1 gene and it corresponds to a highly conserved residue which has been involved in InsP binding in PH domains of other proteins. The same residue is often mutated in the Bruton's tyrosine kinase (Btk) gene in patients with an X-linked agammaglobulinemia. The Arg610Gln mutation represents the first case of a mutation in the PH domain of the FGD1 gene and additional evidence that mutations in PH domains can be associated to human diseases.