X-linkage and manic-depressive illness: a reassessment.

Genetic-epidemiological data and linkage studies with chromosomal markers are reviewed from the vantage point of X-linked inheritance. The results overall suggest that a gene predisposing to manic depression (bipolar affective illness) localized on the X-chromosome may exist in a subgroup of bipolar cases. However, in light of conflicting findings and methodological uncertainties in studying a disorder with unclear phenotype and complex inheritance, this issue is not yet closed. Additional research, including new linkage data and extension and re-evaluation of published data, is required to further our understanding of this intriguing hypothesis.     

mtDNA analysis shows common ancestry in two kindreds with X-linked recessive hypoparathyroidism and reveals a heteroplasmic silent mutation.

Two kindreds residing in eastern Missouri and exhibiting X-linked recessive idiopathic hypoparathyroidism have been described. Genealogical records extending back five generations revealed no common ancestor. To investigate the possibility of relatedness, the DNA sequence of the mitochondrial D-loop was compared among several individuals in both kindreds. The mtDNA D-loop was amplified from the total DNA of individuals by use of nested PCR reactions, and the resulting 430-bp fragment was sequenced. The mtDNA sequence was identical among affected males and their maternal lineage for individuals in both kindreds. Conversely, the mtDNA sequence of the fathers of the affected males differed from that of the maternal lineage at three to six positions. These results demonstrate that the two kindreds exhibiting X-linked recessive hypoparathyroidism are indeed related and that an identical gene defect is responsible for the disease. A further feature of the inheritance pattern was examined when a unique point mutation was identified in the mtDNA of one branch of one of the kindreds. This mutation appears to be de novo and segregates in subsequent generations without obscuring relatedness. In addition, the results of our study of mtDNA analysis indicate that this approach may be of importance in investigating common ancestry in other X-linked disorders.     

The transmission/disequilibrium test for linkage on the X chromosome

The transmission/disequilibrium test (TDT), which detects linkage between a marker and disease loci in the presence of linkage disequilibrium, was introduced by Spielman et al. The original TDT requires families in which the genotypes are known for both parents and for at least one affected offspring, and this limits its applicability to diseases with late onset. The sib-TDT, or S-TDT, which utilizes families with affected and unaffected siblings, was introduced as an alternative method, by Spielman and Ewens, and the TDT and S-TDT can be combined in an overall test (i.e., a combined-TDT, or C-TDT). The TDT statistics described so far are for autosomal chromosomes. We have extended these TDT methods to test for linkage between X-linked markers and diseases that affect either males only or both sexes. For diseases of late onset, when parental genotypes are often unavailable, the X-linkage C-TDT may allow for more power than is provided by the X-linkage TDT alone.     

XY gonadal dysgenesis: Genetic heterogeneity based upon clinical observations,H-Y antigen status and segregation analysis

Summary Clinical observations and segregation analysis indicate that XY gonadal dysgenesis is characterized by genetic heterogeneity. In addition to the type inherited in X-linked recessive fashion, segregation analysis of other families suggested another type by revealing that the proportion of affected sibs did not differ from that expected on the basis of a male-limited autosomal recessive inheritance. Further heterogeneity may be deduced on the basis of coexisting campomelic dwarfism or possibly also renal parenchymal abnormalities. These observations of genetic heterogeneity must be considered when interpreting studies in which individuals with XY gonadal dysgenesis may or may not show H-Y antigen.     

X‐linkage and manic‐depressive illness: A reassessment

Abstract

Genetic‐epidemiological data and linkage studies with chromosomal markers are reviewed from the vantage point of X‐linked inheritance. The results overall suggest that a gene predisposing to manic depression (bipolar affective illness) localized on the X‐chromosome may exist in a subgroup of bipolar cases. However, in light of conflicting findings and methodological uncertainties in studying a disorder with unclear phenotype and complex inheritance, this issue is not yet closed. Additional research, including new linkage data and extension and re‐evaluation of published data, is required to further our understanding of this intriguing hypothesis.     

A test of the hypothesis that age at onset in Huntington disease is controlled by an X-linked recessive modifier.

Data from the Research Roster for Huntington Disease Patients and Families were used to assess the hypothesis that juvenile onset in Huntington disease is determined by an X-linked recessive modifying gene in the affected parent. The observed proportion of affected fathers to affected mothers who had such offspring was not compatible with this hypothesis. Furthermore, neither the excess of affected grandfathers nor the existence of juvenile-onset and adult-onset cases within a sibship would be predicted by this model. We also rejected a more general hypothesis that a major change in gene expression across generations, measured by the presence of juvenile onset and/or major anticipation, is determined by an X-linked modifier. However, the inheritance of a propensity toward juvenile onset via the affected male line could be due to an abnormal pattern of paternal genomic imprinting.     

Evidence against an X-linked locus close to DXS7 determining visual loss susceptibility in British and Italian families with Leber hereditary optic neuropathy.

Leber hereditary optic neuropathy (LHON) is associated with mutations of mtDNA, but two features of LHON pedigrees are not explicable solely on the basis of mitochondrial inheritance. There is a large excess of affected males, and not all males at risk develop the disease. These observations could be explained by the existence of an X-linked visual loss susceptibility gene. This hypothesis was supported by linkage studies in Finland, placing the susceptibility locus at DXS7, with a maximum lod score of 2.48 at a recombination fraction of 0. Linkage studies in 1 Italian and 12 British families with LHON, analyzed either together or separately depending on the associated mtDNA mutation, have excluded the presence of such a locus from an interval of about 30 cM around DXS7 in these kindreds, with a total lod score of -26.51 at a recombination fraction of 0.     

Patterns of maternal transmission in bipolar affective disorder.

The mode of inheritance of bipolar affective disorder (BPAD) appears complex, and non-Mendelian models of inheritance have been postulated. Two non-Mendelian phenomena, genomic imprinting and mitochondrial inheritance, may contribute to the complex inheritance pattern seen in BPAD. Both imprinting and mitochondrial inheritance share the feature of differential expression of the phenotype, depending on the parent of origin. In this study we tested the hypothesis of a parent-of-origin effect on the transmission of BPAD. We examined the frequency and risk of affective disorder among relatives in a sample of 31 families ascertained through treated probands with BPAD and selected for the presence of affected phenotypes in only one parental lineage. Three specific comparisons were performed: (1) the observed frequency of transmitting mothers versus transmitting fathers; (2) the observed frequency and lifetime risk of BPAD among the maternal versus the paternal relatives of probands; and (3) the observed frequency and lifetime risk of BPAD for the offspring of affected mothers compared with the offspring of affected fathers. We observed a higher than expected frequency of affected mothers (P < .04), a 2.3-2.8-fold increased risk of illness for maternal relatives (P < .006), and a 1.3- 2.5-fold increased risk of illness for the offspring of affected mothers (P < .017).In seven enlarged pedigrees, fathers repeatedly failed to transmit the affected phenotype to daughters or sons. Taken together, these findings indicate a maternal effect in the transmission of BPAD susceptibility and suggest that molecular studies of mtDNA and imprinted DNA are warranted in patients with BPAD.     

Sex-linked expression of a sexually selected trait in the stalk-eyed fly, Cyrtodiopsis dalmanni

Recent theoretical and empirical work has suggested that the X chromosome may play a special role in the evolution of sexually dimorphic traits. We tested this idea by quantifying sex chromosome influence on male relative eyespan, a dramatically sexually selected trait in the stalk-eyed fly, Cyrtodiopsis dalmanni. After 31 generations of artificial sexual selection on eyespan:body length ratio, we reciprocally crossed high- with low-line flies and found no evidence for maternal effects; the relative eyespan of F1 females from high- and low-line dams did not differ. However, F1 male progeny from high-line dams had longer relative eyespan than male progeny from low-line dams, indicating X-linkage. Comparison of progeny from a backcross involving reciprocal F1 males and control line females confirmed X-linked inheritance and indicated no effect of the Y chromosome on relative eyespan. We estimated that the X chromosome accounts for 25% (SE = 6%) of the change in selected lines, using the average difference between reciprocal F1 males divided by the difference between parental males, or 34%, using estimates of the number of effective factors obtained from reciprocal crosses between a high and low line. These estimates exceed the relative size of the X in the diploid genome of a male, 11.9% (SE = 0.3%), as measured from mitotic chromosome lengths. However, they match expectations if X-linked genes in males exhibit dosage compensation by twofold hyperactivation, as has been observed in other flies. Therefore, sex-linked expression of relative eyespan is likely to be commensurate with the size of the X chromosome in this dramatically dimorphic species.     

Evidence for X-linkage of phosphoribosylpyrophosphate synthetase in man. Studies with cultured fibroblasts from a gouty family with mutant feedback-resistant enzyme.

Skin fibroblast cultures were utilized to study the mode of inheritance of a mutant feedback-resistant phosphoribosylpyrophosphate synthetase in a gouty family with purine overproduction. Selective conditions were applied to allow the survival in culture of mutant cells only. Whereas in the male gouty propositus the cell culture was homogenous for the mutant enzyme, in the cell culture from his nongouty mother two cell populations were demonstrated, one normal and the other mutant. The mosaicism in the mother is compatible with X-linkage of the enzyme. From this finding, together with the clinical and biochemical data available, it is concluded that in this family the enzyme mutation is transmitted in a X-linked recessive pattern.     

The two locus control of Leber hereditary optic neurophathy and a high penetrance in Japanese pedigrees

The maternal transmission of Leber hereditary optic neuropathy (LHON) can be explained by the mitochondrial DNA mutation. However, the characteristic mode of inheritance, i.e. male predominance and reduced penetrance with late onset in females, suggests the simultaneous involvement of an X-linked gene in development of optic atrophy. We have assessed such a two-locus model of mitocnondrial and X-linked genes in Japanese LHON pedigrees. The goodness-of-fit test on individual male sibship data with a presumed heterozygous mother from maternal lines showed an excellent fit for the 1:1 segregation of a putative X-linked gene, thus supporting the two-locus model in the Japanese pedigrees tested. A calculated frequency of the X-linked gene was 0.10. We could not determine whether the present value is different from the reported one (= 0.08). On the other hand, the estimated penetrance for a heterozygous female was 0.196±0.039, which was about twice as high as the reported value (=0.111) with a 5% level of significance. Such a high penetrance may primarily arise from a low threshold of LHON manifestation, suggesting the ethnic difference between the LHON pedigrees in Japan and in other countries.     

Genetic aspects of febrile convulsions

Summary A total of 6706 children 3 years of age (3491 boys, 3215 girls) in a particular geographical area in Fuchu (population approximately 182 000), Tokyo, was investigated. Some 654 children (9.8%; 10.5% for male, 9.0% for female) had had at least one convulsion, and the incidence of febrile convulsions was 6.7% (7.2% for male, 6.2% for female). The 450 FC children with febrile convulsions and 620 randomly selected control children were analyzed on the mode of inheritance.The incidence of the disease among siblings was 21.9% (29.7% after age correction), which rose greatly with increasing numbers of affected family members, and the segregation ratio among siblings was higher (36.5%) with one FC parent, and lower (18.5%) if neither parent had had a seizure. The more severe the illness in FC children, the larger the incidence among siblings.Population and family studies indicated that heredity plays an important role in febrile convulsions and that multifactorial inheritance is most likely.     

X-linked ichthyosis,due to steroid sulphatase deficiency,associated with Kallmann syndrome (hypogonadotropic hypogonadism and anosmia): linkage relationships with Xg and cloned DNA sequences from the distal short arm of the X chromosome

Summary We report a large Italian pedigree in which five out of six males are affected by a syndrome, following an X-linked inheritance pattern, characterized by ichthyosis, hypogonadotropic hypogonadism, and anosmia. The concurrence of features of X-linked ichthyosis (XLI) with those of Kallmann syndrome, another disease often inherited as an X-linked trait, prompted us to perform biochemical, cytogenetic, and molecular studies in relation to the short arm of the X chromosome (Xp). Steroid sulphatase (STS) activity was found to be completely deficient in all affected members of the family. Prometaphase chromosome analyses of two obligate heterozygous women and one affected male showed normal karyotypes. Xg blood group antigen analysis and molecular studies employing cloned DNA sequences from the distal segment of the Xp (probes RC8, 782, dic56, and M1A), did not provide evidence for deletions or rearrangements of the X chromosome. The linkage analysis showed no crossovers between the disease, Xg, and DXS 143, the locus defined by probe dic56, thus suggesting the possibility of a linkage between these two markers of the distal segment of Xp and the X-linked ichthyosis, hypogonadism, and anosmia syndrome.     

Studies of X-chromosome inactivation with an improved histochemical technique for ornithine carbamoyltransferase

Studies of X-linked enzymes provide an approach to the study of tumour and normal cellular development. We have assessed the technique for the histochemical demonstration of one such enzyme, ornithine carbamoyltransferase (EC 2.1.3.3). Various stages in the Mizutani technique for ornithine carbamoyltransferase were re-examined, and the resulting improved technique applied to normal mice and to mice of the sparse fur strain (Spf) known to have an abnormal form of ornithine carbamoyltransferase inherited as an X-linked characteristic. Positive enzyme activity was present in all hepatocytes from normal mice, the strongest reaction being present in the periportal area with a gradual reduction of activity towards the centrilobular region. No activity was demonstrable in hepatocytes from hemizygous male Spf mice. In heterozygous female Spf mice, there was a clear-cut separation of ornithine carbamoyl-transferase-positive and -negative cells. These were present in very variable proportions in different liver lobes and different animals. Preliminary studies were also carried out using a high pH reaction mixture to detect the abnormal enzyme. These studies demonstrate conclusively the X-linkage of ornithine carbamoyltransferase in mice, showing the mosaic pattern of distribution predicted by the Lyon hypothesis. They show that the Spf strain of mice can be used for studies of both development and tumorigenesis in the liver, and that histochemical study of an animal strain with an X-linked enzyme abnormality provides a powerful investigative tool.     

Segregation analysis in Shwachman-Diamond syndrome: evidence for recessive inheritance

Shwachman-Diamond syndrome is a rare disorder of unknown cause. Reports have indicated the occurrence of affected siblings, but formal segregation analysis has not been performed. In families collected for genetic studies, the mean paternal age and mean difference in parental ages were found to be consistent with the general population. We determined estimates of segregation proportion in a cohort of 84 patients with complete sibship data under the assumption of complete ascertainment, using the Li and Mantel estimator, and of single ascertainment with the Davie modification. A third estimate was also computed with the expectation-maximization (EM) algorithm. All three estimates supported an autosomal recessive mode of inheritance, but complete ascertainment was found to be unlikely. Although there are no overt signs of disease in adult carriers (parents), the use of serum trypsinogen levels to indicate exocrine pancreatic dysfunction was evaluated as a potential measure for heterozygote expression. No consistent differences were found in levels between parents and a normal control population. Although genetic heterogeneity cannot be excluded, our results indicate that simulation and genetic analyses of Shwachman-Diamond syndrome should consider a recessive model of inheritance.     

MAINTENANCE OR LOSS OF GENETIC VARIATION UNDER SEXUAL AND PARENTAL ANTAGONISM AT A SEX-LINKED LOCUS

An intralocus genetic conflict occurs when a locus is selected in opposing directions in different subsets of a population. Populations with two sexes have the potential to host a pair of distinct intralocus conflicts: sexual antagonism and parental antagonism. In this article, we examine the population genetic consequences of these conflicts for X-linked genes. Both conflicts are capable of maintaining genetic variation in a population, but to different degrees. For weak sexual antagonism, the X chromosome has a higher opportunity for polymorphism than the autosomes. For parental antagonism, there is a very limited opportunity for polymorphism on the X chromosome relative to autosomes or to sexual antagonism. X-linkage introduces an asymmetry in the inheritance and expression of sexually and parentally antagonistic genes that leads to a biased fixation of alleles with certain effects. We find little support for the commonly held intuition that the X chromosome should be biased toward fixing female-beneficial alleles. Contrary to this intuition, we find that the X chromosome is biased toward fixation of male-beneficial alleles for much of the range of dominance. Additionally, we find that the X chromosome is more favorable to the fixation of alleles that are beneficial when maternally derived.     

Linkage relationships of X-linked choroideremia to DXYS1 and DXS3

Summary Choroideremia is a distinct blinding condtion with an X-linked pattern of inheritance. We have analyzed two RFLPs, DXS3 and DXYS1, for linkage with the choroideremia locus (TCD) within three kindreds. A maximum LOD score of 3.98 was obtained at . Contrary to previous reports, the present data demonstrate that these two RFLPs are not tightly linked to the choroideremia gene locus.     

Mapping of a further locus for X-linked craniofrontonasal syndrome

Craniofrontonasal syndrome is a rare dysostosis syndrome with an unusual pattern of X-linked inheritance, because males are usually not or less severely affected than females. Previously, a CFNS locus has been localised in Xp22. We report on a haplotype analysis in a German CFNS family, mapping the CFNS locus to the pericentromeric region of the X chromosome. This discrepancy can be explained by locus heterogeneity. Furthermore, random X inactivation could be demonstrated in affected females. The most plausible interpretation for this unusual pattern of X-linked inheritance is metabolic interference. Consequently, we propose that the CFNS gene escapes X inactivation.     

A comprehensive mutation analysis of RP2 and RPGR in a North American cohort of families with X-linked retinitis pigmentosa

X-linked retinitis pigmentosa (XLRP) is a clinically and genetically heterogeneous degenerative disease of the retina. At least five loci have been mapped for XLRP; of these, RP2 and RP3 account for 10%-20% and 70%-90% of genetically identifiable disease, respectively. However, mutations in the respective genes, RP2 and RPGR, were detected in only 10% and 20% of families with XLRP. Mutations in an alternatively spliced RPGR exon, ORF15, have recently been shown to account for 60% of XLRP in a European cohort of 47 families. We have performed, in a North American cohort of 234 families with RP, a comprehensive screen of the RP2 and RPGR (including ORF15) genes and their 5' upstream regions. Of these families, 91 (39%) show definitive X-linked inheritance, an additional 88 (38%) reveal a pattern consistent with X-linked disease, and the remaining 55 (23%) are simplex male patients with RP who had an early onset and/or severe disease. In agreement with the previous studies, we show that mutations in the RP2 gene and in the original 19 RPGR exons are detected in <10% and approximately 20% of XLRP probands, respectively. Our studies have revealed RPGR-ORF15 mutations in an additional 30% of 91 well-documented families with X-linked recessive inheritance and in 22% of the total 234 probands analyzed. We suggest that mutations in an as-yet-uncharacterized RPGR exon(s), intronic changes, or another gene in the region might be responsible for the disease in the remainder of this North American cohort. We also discuss the implications of our studies for genetic diagnosis, genotype-phenotype correlations, and gene-based therapy.