X chromosome inactivation and X-linked mental retardation

The expression of X-linked genes in females heterozygous for X-linked defects can be modulated by epigenetic control mechanisms that constitute the X chromosome inactivation pathway. At least four different effects have been found to influence, in females, the phenotypic expression of genes responsible for X-linked mental retardation (XLMR). First, non-random X inactivation, due either to stochastic or genetic factors, can result in tissues in which one cell type (for example, that in which the X chromosome carrying a mutant XLMR gene is active) dominates, instead of the normal mosaic cell population expected as a result of random X inactivation. Second, skewed inactivation of the normal X in individuals carrying a deletion of part of the X chromosome has been documented in a number of mentally retarded females. Third, functional disomy of X-linked genes that are expressed inappropriately due to the absence of X inactivation has been found in mentally retarded females with structurally abnormal X chromosomes that do not contain the X inactivation center. And fourth, dose-dependent overexpression of X-linked genes that normally “escape” X inactivation may account for the mental and developmental delay associated with increasing numbers of otherwise inactive X chromosomes in individuals with X chromosome aneuploidy. © 1996 Wiley-Liss, Inc.     

Familial X-linked mental retardation with a marker X chromosome and its relationship to macro-orchidism

It has been suggested that the form of X-linked mental retardation with macro-orchidism and the form associated with a marker X chromosome (fragile site at Xq27 or 28) are the Same entity. Although our data support this hypothesis, one family from the literature does not. Data are presented suggesting that actual measurements are required for accurate evaluation of testicular size.     

Familial X-linked mental retardation and fragile X chromosomes in two Swedish families

X-linked mental retardation (MR) associated with a fragile X chromosome was found in two Swedish families. The fragile X chromosome was demonstrated in 5/5 boys with mental retardation. Clinical data on four of these boys are presented. In one of the families, the mental retardation was associated with macro-orchidism, large hands and large, folded ears. In the other family, macro-orchidism was not seen, possibly because the boys were younger. Fragile site X chromosomes were also seen in three obligate carriers. A summary of earlier published cases of X-linked MR associated with the fragile X chromosome is given.     

X chromosome array-CGH for the identification of novel X-linked mental retardation genes

Array-CGH technology for the detection of submicroscopic copy number changes in the genome has recently been developed for the identification of novel disease-associated genes. It has been estimated that submicroscopic genomic deletions or duplications will be present in 5-7% of patients with idiopathic mental retardation (MR). Since 30% more males than females are diagnosed with MR, we have developed a full coverage X chromosome array-CGH with a theoretical resolution of 82 kb, for the detection of copy number alterations in patients with suspected X-linked mental retardation (XLMR). First, we have validated the genomic location of X-derived clones through male versus female hybridisations. Next, we validated our array for efficient and reproducible detection of known alterations in XLMR patients. In all cases, we were able to detect the deletions and duplications in males as well as females. Due to the high resolution of our X-array, the boundaries of the genomic aberrations could clearly be identified making genotype-phenotype studies more reliable. Here, we describe the production and validation of a full coverage X-array-CGH, which will allow for fast and easy screening of submicroscopic copy number alterations in XLMR patients with the aim to identify novel MR genes or mechanisms involved in a deranged cognitive development.     

Familial mental retardation in a family with an inherited chromosome rearrangement

A family of three generations has been described with an insertional type of chromosome rearrangement involving chromosomes 11 and 18[46,XX or XY, ins(11;18)(p15;q11q21)] detected by G-banding using a trypsin digestion method. Four members of this family with clinical features of 18q− have inherited the der(18) from their father and are thus deficient for (18)(q11q21). Three other family members have inherited the der(11) and thus have a duplication of the same segment [(18)(q11q21)]. Genetic marker studies on this family, show no significant segregation of any of the markers studied with either the der(11) or der(18). Eight family members had the PepA⁸PepA¹ genotype and four of these were carrying the der(18), indicating that the PepA locus which had been previously assigned to chromosome 18, does not lie in the segment q11→q21.     

X-linked mental retardation associated with macro-orchidism.

Two families are described with an X-linked form of mental retardation in whom the affected males were found to have bilateral enlargement of the testes. No conclusive evidence of any endocrinological disturbance was found.     

X-linked mental retardation

A survey of the mentally retarded children with an IQ between 30 and 55 born in a 10-year period (1955-64) and now of school age was carried out in New South Wales. The number of propositi who had a similarly affected sib of the same sex was ascertained; 58 boys had a similarly affected brother(s) and 22 girls had a similarly affected sister(s). It is suggested that the excess of affected brothers represents X-linked forms of mental retardation. An estimate of prevalence rate was calculated from the brother pair excess and was found to be 0·74/1000 males. The calculated incidence of X-linked forms of mental retardation appeared to account for most of the male excess found in the survey and suggests that 1 in every 5 of the mentally retarded boys in the IQ range in this survey may be retarded on the basis of genes on the X chromosome.     

Familial mental retardation

Familial patterns of mental retardation were examined among white and black children in the NINCDS Collaborative Perinatal Project population. Among whites, the mildly retarded children had more affected relatives than did the severely retarded, consistent with the traditional two-group theory of mental retardation. In blacks, where differences in family patterns between the mildly and the severely retarded were less clear, most retardation appeared to be of the cultural-familial type.     

Screening of 20 patients with X-linked mental retardation using chromosome X-specific array-MAPH

The rapid advancement of high-resolution DNA copy number assessment methods revealed the significant contribution of submicroscopic genetic imbalances to abnormal phenotypes, including mental retardation. In order to detect submicroscopic genetic imbalances, we have screened 20 families with X-linked mental retardation (XLMR) using a chromosome X-specific array-MAPH platform with median resolution of 238 kb. Among the 20 families, 18 were experimental, as they were not previously screened with any microarray method, and two were blind controls with known aberrations, as they were previously screened by array-CGH. This study presents the first clinical application of chromosome X-specific array-MAPH methodology. The screening of 20 affected males from 20 unrelated XLMR families resulted in the detection of an unknown deletion, spanning a region of 7–23 kb. Family studies and population screening demonstrated that the detected deletion is an unknown rare copy number variant. One of the control samples, carrying approximately 6-Mb duplication was correctly identified, moreover it was found to be interrupted by a previously unknown 19 kb region of normal copy number. The second control 50 kb deletion was not identified, as this particular region was not covered by array-MAPH probes. This study demonstrates that the chromosome X-specific array-MAPH platform is a valuable tool for screening patients with XLMR, or other X-linked disorders, and emerges the need for introducing new high-resolution screening methods for the detection of genetic imbalances.     

International workshop on the fragile X and X-linked mental retardation

The erythrocyte osmotic fragility was evaluated on 19 unmedicated subjects with Huntington's disease and 42 individuals at 50% risk, 27 children at 25% risk, and a group of 60 hematologically normal control persons. Five older subjects at 50% risk for Huntington's disease as well as 6 Alzheimer's disease individuals were also evaluated for comparison. The osmotic fragility of fresh and 24-hour incubated red cells was analyzed and a fragility index calculated for each individual. The fragility index for the Huntington's disease group was statistically lower than that of the control group (P < .001) suggesting that the Huntington's disease erythrocytes had a reduced osmotic fragility. In the 50% risk group, 45% of the subjects demonstrated decreased osmotic fragility and 55% had normal fragility. For those subjects in the 25% risk group, 22.2% had decreased fragility and 77.8% had normal fragility. Twenty-seven offspring were evaluated of the 14 persons at 50% risk for Huntington's disease with children; eight of the 14 individuals at 50% risk showed normal fragility and all 16 of their children showed fragility indices with the normal range. The remaining six persons at 50% risk for Huntington's disease had increased erythrocyte fragility and out of their 11 children, five showed normal fragility and six had decreased fragility. These data support the hypothesis of reduced erythrocyte osmotic fragility in individuals affected with and at risk for Huntington disease, and demonstrate the need of further study of the erythrocyte in this complex behavioral genetic disease.     

A large kindred with X-linked mental retardation, marker X and macroorchidism

Thirty-eight members of a black kindred with mental retardation and the Marker X were studied. Ten of 14 affected males, 6 of 6 affected females, 18 carriers or possible carriers, and 7 normal males were examined. Eight of 9 affected males who could be measured had macroorchidism, but their ears and mandibles were not prominent. No distinct facies were evident, although minor anomalies, such as a slight pectus, were present in some. Clinical diagnosis in the absence of a strongly positive family history may be even more difficult among prepubertal black children than in whites. The risk of retardation among children of carriers was estimated at 20-40%.     

X-linked dysmorphic syndrome with mental retardation

We present a dysmorphic syndrome in eight males of the same family (four brothers, three cousins and one uncle) that is characterised by: mental retardation, facial dysmorphia, abnormal growth of teeth, skin dimple at the lower back, clinodactyly, patella luxation, malformation of lower limbs, abnormalities of the fundus of the eye and subcortical cerebral atrophy. These physical defects do not correspond to any previously described syndrome, which suggests that it is a new syndrome. According to the model of heredity this syndrome could be due to a mutant gene situated in the X-chromosome.     

X-linked mental retardation with marfanoid habitus

Here we report on two pairs of mildly to moderately mentally retarded brothers with marfanoid habitus and similar craniofacial changes. They had a long and narrow face, small mandible, high-arched palate, and hypernasal voice, as previously reported by Lujan et al (Am J Med Genet 17:311-322, 1984) in four mentally retarded males of a large kindred. The present data suggest the existence of a specific type of X-linked mental retardation with marfanoid habitus.     

X-linked skeletal dysplasia with mental retardation

A syndrome compatible with an X-linked trait is described, affecting four male cousins in three sibships. The boys had skeletal anomalies, including short stature, ridging of the metopic suture, fusion of cervical vertebrae, thoracic hemivertebrae, scoliosis, sacral hypoplasia and short middle phalanges. In addition, they had moderate developmental retardation, and abducens palsies. Three of the four had glucose intolerance, and one was born with an imperforate anus.
Of five female obligate carriers studied, three had fusion of cervical vertebrae, three had some shortening of the middle phalanges and three had glucose intolerance.
The syndrome in this family was compared to previously reported syndromes, and the conclusion was reached that it represents a previously unreported X-linked syndrome with minor manifestations in carrier females.