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The X-chromosome comprises only about 5% of the human genome but accounts for about 15% of the genes currently known to be associated with intellectual disability. The early progress in identifying the X-linked intellectual disability (XLID)-associated genes through linkage analysis and candidate gene sequencing has been accelerated with the use of high-throughput technologies. In the 10 years since the last update, the number of genes associated with XLID has increased by 96% from 72 to 141 and duplications of all 141 XLID genes have been described, primarily through the application of high-resolution microarrays and next generation sequencing. The progress in identifying genetic and genomic alterations associated with XLID has not been matched with insights that improve the clinician's ability to form differential diagnoses, that bring into view the possibility of curative therapies for patients, or that inform scientists of the impact of the genetic alterations on cell organization and function., (© 2018 Wiley Periodicals, Inc.)

X-Linked intellectual disability (XLID) accounts for 5%-10% of intellectual disability in males. Over 150 syndromes, the most common of which is the fragile X syndrome, have been described. A large number of families with nonsyndromal XLID, 95 of which have been regionally mapped, have been described as well. Mutations in 102 X-linked genes have been associated with 81 of these XLID syndromes and with 35 of the regionally mapped families with nonsyndromal XLID. Identification of these genes has enabled considerable reclassification and better understanding of the biological basis of XLID. At the same time, it has improved the clinical diagnosis of XLID and allowed for carrier detection and prevention strategies through gamete donation, prenatal diagnosis, and genetic counseling. Progress in delineating XLID has far outpaced the efforts to understand the genetic basis for autosomal intellectual disability. In large measure, this has been because of the relative ease of identifying families with XLID and finding the responsible mutations, as well as the determined and interactive efforts of a small group of researchers worldwide., (Copyright © 2012 The American Society of Human Genetics. Published by Elsevier Inc. All rights reserved.)

Allan-Herndon-Dudley syndrome was among the first of the X-linked mental retardation syndromes to be described (in 1944) and among the first to be regionally mapped on the X chromosome (in 1990). Six large families with the syndrome have been identified, and linkage studies have placed the gene locus in Xq13.2. Mutations in the monocarboxylate transporter 8 gene (MCT8) have been found in each of the six families. One essential function of the protein encoded by this gene appears to be the transport of triiodothyronine into neurons. Abnormal transporter function is reflected in elevated free triiodothyronine and lowered free thyroxine levels in the blood. Infancy and childhood in the Allan-Herndon-Dudley syndrome are marked by hypotonia, weakness, reduced muscle mass, and delay of developmental milestones. Facial manifestations are not distinctive, but the face tends to be elongated with bifrontal narrowing, and the ears are often simply formed or cupped. Some patients have myopathic facies. Generalized weakness is manifested by excessive drooling, forward positioning of the head and neck, failure to ambulate independently, or ataxia in those who do ambulate. Speech is dysarthric or absent altogether. Hypotonia gives way in adult life to spasticity. The hands exhibit dystonic and athetoid posturing and fisting. Cognitive development is severely impaired. No major malformations occur, intrauterine growth is not impaired, and head circumference and genital development are usually normal. Behavior tends to be passive, with little evidence of aggressive or disruptive behavior. Although clinical signs of thyroid dysfunction are usually absent in affected males, the disturbances in blood levels of thyroid hormones suggest the possibility of systematic detection through screening of high-risk populations.

Renpenning syndrome represents a prototypic X-linked mental retardation condition with full expression of the phenotype in males and little or no expression in females. The predominant clinical findings are microcephaly, long narrow face, short stature with lean body build, and small testes. Mental retardation, usually of severe degree, occurs in 95% of cases. Less than 20% of cases have major malformations, the most common being cardiac defects and cleft palate. Subsequent to the description of mutations in the polyglutamine tract binding protein 1 (PQBP1) in Sutherland-Haan syndrome, Hamel cerebropalatocardiac syndrome, MRX55, and two small XLMR families, a single nucleotide insertion has been found in the original family with Renpenning syndrome and an AGAG deletion in a second family with the Renpenning syndrome. Mutations have also been found in Golabi-Ito-Hall syndrome, Porteous syndrome, and an additional small family. It is now demonstrated that five named XLMR syndromes (Sutherland-Haan, Hamel cerebropalatocardiac, Golabi-Ito-Hall, Porteous, and Renpenning), one nonsyndromic family (MRX55), and three small XLMR families have PQBP1 mutations and are thus allelic XLMR entities. In acknowledgement of the historical importance of the original report of Renpenning syndrome [1962], we propose that the entities with PQBP1 mutations be combined under the name of Renpenning syndrome., (2005 Wiley-Liss, Inc.)

The renin-angiotensin system (RAS) is essential for blood pressure control and water-electrolyte balance. Until the discovery of the renin receptor, renin was believed to be mainly a circulating enzyme with a unique function, the cleavage of angiotensinogen. We report a unique mutation in the renin receptor gene (ATP6AP2) present in patients with X-linked mental retardation and epilepsy (OMIM no. 300423), but absent in 1200 control X-chromosomes. A silent mutation (c.321C>T, p.D107D) residing in a putative exonic splicing enhancer site resulted in inefficient inclusion of exon 4 in 50% of renin receptor mRNA, as demonstrated by quantitative RT-PCR. Analysis of membrane associated-receptor molecular forms showed the presence of full-length and truncated proteins in the patient. Functional analysis demonstrated that the mutated receptor could bind renin and increase renin catalytic activity, similar to the wild-type receptor, but resulted in a modest and reproducible impairment of ERK1/2 activation. Thus, our findings confirm the importance of the RAS in cognitive processes and indicate a novel specific role for the renin receptor in cognitive functions and brain development.

The Chudley-Lowry syndrome (ChLS, MIM 309490) is an X-linked recessive condition characterized by moderate to severe mental retardation, short stature, mild obesity, hypogonadism, and distinctive facial features characterized by depressed nasal bridge, anteverted nares, inverted-V-shaped upper lip, and macrostomia. The original Chudley-Lowry family consists of three affected males in two generations. Linkage analysis had localized the gene to a large interval, Xp21-Xq26 and an obligate carrier was demonstrated to have highly skewed X inactivation. The combination of the clinical phenotype, consistent with that of the patients with ATR-X syndrome, the skewed X-inactivation pattern in a carrier female, as well as the mapping interval including band Xq13.3, prompted us to consider the XNP/ATR-X gene being involved in this syndrome. Using RT-PCR analysis, we screened the entire XNP/ATR-X gene and found a mutation in exon 2 (c.109C > T) giving rise to a stop codon at position 37 (p.R37X). Western blot and immunocytochemical analyses using a specific monoclonal antibody directed against XNP/ATR-X showed the protein to be present in lymphoblastoid cells from one affected male, despite the premature stop codon. To explain these discordant results, we further analyzed the 5' region of the XNP/ATR-X gene and found three alternative transcripts, which differ in the presence or absence of exon 2, and the length of exon 1. Our data suggest that ChLS is allelic to the ATR-X syndrome with its less severe phenotype being due to the presence of some XNP/ATR-X protein.

Mental retardation (MR) affects an estimated 2-3% of the population. A considerable fraction of mental retardation is due to X-linked genes. Of these genes, about 136 are responsible for syndromic X-linked MR (XLMR). One such XLMR syndrome, Stocco dos Santos, was first described in 1991. This family was re-visited, which allowed further delineation of the clinical phenotype. Additionally, linkage analysis was conducted, which resulted in the localization of this XLMR syndrome to the pericentric region, Xp11.3 to Xq21.1, with a maximum LOD score of 3.14 at loci AR and DXS983., (Copyright 2003 Wiley-Liss, Inc.)

This report describes a family with mental retardation in two brothers. The pedigree is consistent with either X-linked mental retardation or autosomal recessive inheritance. The clinical features consist of coarse face, prominent lower lip, large testes, and obesity. This same constellation of findings was observed in a family with X-linked mental retardation (XLMR) reported by Shashi et al. [2000: Am J Hum Genet 66:469-479]. Furthermore, haplotype analysis was consistent with localization of the Shashi XLMR syndrome in Xq26-q27. Thus, the family likely represents a second occurrence of the Shashi XLMR syndrome., (Copyright 2003 Wiley-Liss, Inc.)

Some deleterious X-linked mutations may result in a growth disadvantage for those cells in which the mutation, when on the active X chromosome, affects cell proliferation or viability. To explore the relationship between skewed X-chromosome inactivation and X-linked mental retardation (XLMR) disorders, we used the androgen receptor X-inactivation assay to determine X-inactivation patterns in 155 female subjects from 24 families segregating 20 distinct XLMR disorders. Among XLMR carriers, approximately 50% demonstrate markedly skewed X inactivation (i.e., patterns > or =80:20), compared with only approximately 10% of female control subjects (P<.001). Thus, skewed X inactivation is a relatively common feature of XLMR disorders. Of the 20 distinct XLMR disorders, 4 demonstrate a strong association with skewed X inactivation, since all carriers of these mutations demonstrate X-inactivation patterns > or =80:20. The XLMR mutations are present on the preferentially inactive X chromosome in all 20 informative female subjects from these families, indicating that skewing is due to selection against those cells in which the XLMR mutation is on the active X chromosome.

A family with X-linked mental retardation characterized by severe mental retardation, speech and behavioral abnormalities, and seizures in affected male patients has been found to have a G1141C transversion in the creatine-transporter gene SLC6A8. This mutation results in a glycine being replaced by an arginine (G381R) and alternative splicing, since the G-->C transversion occurs at the -1 position of the 5' splice junction of intron 7. Two female relatives who are heterozygous for the SLC6A8 mutation also exhibit mild mental retardation with behavior and learning problems. Male patients with the mutation have highly elevated creatine in their urine and have decreased creatine uptake in fibroblasts, which reflects the deficiency in creatine transport. The ability to measure elevated creatine in urine makes it possible to diagnose SLC6A8 deficiency in male patients with mental retardation of unknown etiology.

Methods: A large family is described in which mental retardation segregates as an X linked trait. Six affected males in three generations were studied by linkage and clinical examination., Results: Characteristic clinical features include short stature, prominent lower lip, small testes, muscle wasting of the lower legs, kyphosis, joint hyperextensibility, abnormal gait, tremor, and decreased fine motor coordination. Affected subjects also had impaired speech and decreased attention span. A carrier female was mildly affected. A similar disorder was not found on review of our XLMR Database of 124 syndromes. Linkage analysis of 37 markers resulted in a lod score of 2.80 at DXS1212 and 2.76 at DXS425. The limiting markers were DXS424 and DXS1047. Ten of 124 XLMR syndromes and eight of 58 MRX families overlap this region., Conclusions: In summary, this family appears to have a new XLMR syndrome localising to Xq24-q25.

Developmental dyslexia is a specific reading disability affecting children and adults who otherwise possess normal intelligence, cognitive skills, and adequate schooling. Difficulties in spelling and reading may persist through adult life. Possible localisations of genes for dyslexia have been reported on chromosomes 15 (DYX1), 6p21.3-23 (DYX2), and 1p over the last 15 years. Only the localisation to 6p21.3-23 has been clearly confirmed and a genome search has not previously been carried out. We have investigated a large Norwegian family in which dyslexia is inherited as an autosomal dominant trait. A genome wide search for linkage with an average 20 cM marker density was initiated in 36 of the 80 family members. The linkage analysis was performed under three different diagnostic models. Linkage analysis in the family identified a region in 2p15-p16 which cosegregated with dyslexia. Maximum lod scores of 3.54, 2.92, and 4.32 for the three different diagnostic models were obtained. These results were confirmed by a non-parametric multipoint GENEHUNTER analysis in which the most likely placement of the gene was in a 4 cM interval between markers D2S2352 and D2S1337. Localisation of a gene for dyslexia to 2p15-16, together with the confirmed linkage to 6p21.3-23, constitute strong evidence for genetic heterogeneity in dyslexia. Since no gene for dyslexia has been isolated, little is known about the molecular processes involved. The isolation and molecular characterisation of this newly reported gene on chromosome 2 (DYX3) and DYX1 will thus provide new and exciting insights into the processes involved in reading and spelling.

We studied a family with 11 males having X-linked mental retardation (XLMR) using microsatellite markers. Aside from the mental retardation, the affected males do not appear to differ from their unaffected brothers or uncles. The gene for this XLMR condition has been linked to DXS451 in Xp22.13 with a lod score of 5.18 at straight theta = 0. Recombination was detected at DXS992 (Xp21.3) and DXS1053 (Xp22.2), thereby defining the limits of the localization. This family is considered to have nonsyndromic XLMR and has been assigned the designation MRX32., (Copyright 1999 Wiley-Liss, Inc.)

Clinical and molecular studies are reported on a family with X-linked mental retardation (XLMR) in which there are eight affected males in three generations. Although the males have somatic manifestations, these are variable and in most cases do not allow clear distinction of affected and unaffected males. Affected males are shorter and have a smaller head circumference. Several also have a sloping forehead (5/8), hearing loss (3/8), cupped ears (2/8), and small testes (4/6). An LOD score of 4.41 with zero recombination was obtained at locus DXS1166 in Xq13.2. This family highlights the difficulty in classifying XLMR conditions as either nonsyndromic or syndromic because of the variable somatic manifestations observed in the affected males., (Copyright 1999 Wiley-Liss, Inc.)

Of the gene-rich regions of the human genome, Xq28 is the most densely mapped. Mutations of genes in this band are responsible for 10 syndromal forms of mental retardation and 5 nonsyndromal forms. Clinical and molecular studies reported here add an additional syndromic form of X-linked mental retardation (XLMR) to this region. The condition comprises short stature, small hands and feet, seizures, cleft palate, and glaucoma. One affected male died at age 19 years in status epilepticus, but others have survived to old age. Carrier females do not have somatic anomalies or mental impairment. The gene is localized to the terminal 8 Mb of Xq28 with markers distal to DXS8011 showing linkage to the disorder with a lod score of 2.11 at zero recombination., (Copyright 1999 Wiley-Liss, Inc.)

The computer database on X-linked mental retardation (XLMR) disorders developed by Arena and Lubs in 1991 has now been updated to include all currently known XLMR disorders and nonspecific (MRX) families. Currently, it includes 123 syndromes, 59 nonspecific XLMR families, and 60 families from the Miami/Greenwood study. The older clinical reports have been reviewed and revised. The search mechanism has also been revised and now includes 740 individual "keywords." Each of these keywords recognizes several of clinical descriptive terms, as used in published literature reports. Searches can be made according to any clinical finding or combination of findings. For each disorder, the database presents a graphic display that contains a revised and more complete set of clinical findings, references, keywords, map localization, molecular information, access to pictures, and OMIM number., (Copyright 1999 Wiley-Liss, Inc.)

We identified a family with three males in two generations with moderate mental retardation. The two oldest were first cousins whose mothers were sisters. The third affected was a grandson through a daughter of one of the sisters, strongly suggesting X- linked inheritance. The affected males had prominent glabella, synophrys, prognathism, generalized hirsutism, and bilateral single palmar creases. All developed seizures in childhood. The two oldest have had a slow deterioration in neurological status with poor gait and balance and progressive weakness. No deterioration in their mental status has been observed. The oldest had cerebellar atrophy confirmed on computed tomography and magnetic resonance imaging scans of the brain and prolonged nerve conduction velocity. Two of the males had hypogammaglobulinemia (IgA deficient). Two-point linkage analysis using 27 microsatellite markers on the X chromosome resulted in a maximum LOD score of 2.23 at straight theta = 0 for locus DSX101. Recombination was observed at locus DSX1170 in Xq21.33 and locus DXS8067 in Xq23. We conclude that this family represents an X-linked disorder associated with a recognizable phenotype, progressive neurological deterioration, and variable hypogammaglobulinemia. The gene appears to lie between Xq21.33 and Xq23., (Copyright 1999 Wiley-Liss, Inc.)

Mutations in genes on the X chromosome are believed to be responsible for the excess of males among individuals with mental retardation. Such genes are numerous, certainly >100, and cause both syndromal and nonsyndromal types of mental retardation. Clinical and molecular studies have been conducted on the Mennonite family with X-linked mental retardation (XLMR) reported, in 1962, by Renpenning et al. The clinical phenotype includes severe mental retardation, microcephaly, up-slanting palpebral fissures, small testes, and stature shorter than that of nonaffected males. Major malformations, neuromuscular abnormalities, and behavioral disturbances were not seen. Longevity is not impaired. Carrier females do not show heterozygote manifestations. The syndrome maps to Xp11.2-p11.4, with a maximum LOD score of 3.21 (recombination fraction 0) for markers between DXS1039 and DXS1068. Renpenning syndrome (also known as "MRXS8"; gene RENS1, MIM 309500) shares phenotypic manifestations with several other XLMR syndromes, notably the Sutherland-Haan syndrome. In none of these entities has the responsible gene been isolated; hence, the possibility that two or more of them may be allelic cannot be excluded at present.

Efforts to understand the genetic basis of mental retardation are greatly assisted by the identification of families with multiple relatives with mental retardation that clinical geneticists encounter in the routine practice of their profession. Here we describe a linkage study of a four generation family in which X linked recessive mental retardation (XLMR) is associated with minor dysmorphism and premature death of the affected males. Microsatellite based polymorphic loci evenly spaced over the entire X chromosome were used initially to detect linkage to Xq28. Further analysis identified a haplotype of Xq28 markers bounded proximally by locus DXS1113 and distally by DXS1108 that cosegregated with XLMR in this family. Two point lod scores > 3.0 provided strong evidence that the gene locus responsible for XLMR in this family is within this 7 Mb region of Xq28. The minor anomalies noted in some affected males were not distinctive enough to suggest a unique syndrome. None of our patients had features of the Waisman-Laxova syndrome or the PPM-X syndrome. The possibility of allelism with any of the five other non-specific XLMR syndromes (MRX3, MRX16, MRX25, MRX28, and MRX41) mapped to Xq28 could not be excluded. While the recognition of a gene responsible for this disorder needs much additional work, multiple female relatives at risk in this family benefit immediately from knowing their genotype and heterozygotes will have the opportunity to undergo prenatal diagnosis.

Compared to maternal exposures, little attention has been paid to the possibility of paternally induced adverse effects on fetal development. There is increasing concern, however, about the potential for male-mediated developmental toxicity brought about by exposure to teratogenic agents. This is evidenced by the number of calls regarding paternal exposures that are received by teratogen information services. In this paper, we report the experience of the state of Florida's Teratogen Information Services regarding questions asked about paternal exposures, and briefly review what is known about the risk of paternal exposure to the 10 agents which are most frequently queried.

A syndrome with distinctive facies, poor muscle tone, absent deep tendon reflexes, tapered fingers, excessive fingerprint arches, genu valgum and mild-moderate mental retardation has occurred in four males in two generations of a white family of European ancestry. The facies are characterised by square configuration, tented upper lip, and thickening of the helices, upper eyelids, and alae nasi. At birth and at maturity, growth (head circumference, height, weight) of affected males is comparable to or greater than unaffected male sibs. Moderate impairment of cognitive function was documented (IQ scores between 40-51). Carriers show no heterozygote manifestations. This X linked condition appears to be different from other syndromes with mental retardation, although there are certain similarities with the alpha thalassaemia-mental retardation syndrome (ATR-X). Linkage analysis found tight linkage to DXS1166 and DXS995 in Xq13 and Xq21 respectively.

A family with a newly detected X-linked syndrome including sensorineural deafness, mental retardation, dystonia and blindness was examined with full-field electroretinography in order to order to find out if the blindness was caused by a retinal degeneration. Six affected males and 2 obligate carriers showed no signs of retinal degeneration. One of 7 affected males had central areolar choroidal dystrophy confirmed by central scotomas in visual fields and an electroretinographic pattern consisting of an attenuated amplitude as well as a prolonged implicit time of the cone b-wave on stimulation with 30 Hz flickering white light.

The gene responsible for nonsyndromic mental retardation in a family with 7 affected males has been localized to Xp21. The maximal two-point lod score was 3.31 for tight linkage to marker DXS1202 in Xp21.3-p22.3 with crossovers between the 3' portion of the DMD gene (DXS1234) proximally and locus DXS989 distally. The XLMR gene in this family has been assigned the designation MRX29. The localization overlaps with at least six other MRX entities linked to the distal short arm of the X chromosome.

The initial goal of this study was to localize as many genes as possible that lead to syndromic and nonspecific XLMR. More recently, this goal has been redefined to include narrowing these localizations and cloning specific genes. In the last 5 years, 61 families have participated in this study; 34 have a projected or actual lod score greater than 2.0. Restudy of 12 families reported previously has been a particularly productive aspect of this study and has led to clinical redefinition and new or improved localization of most of these syndromes. Five possible new XLMR syndromes have been identified. Five large families with nonspecific XLMR have been regionally localized. Since many XLMR conditions are based on only 1 or 2 family reports, one of the major purposes of this summary is to provide clinical data on the study families so that collaborative projects can be undertaken with other centers that have similar families.

A current list of all known forms of X-linked mental retardation (XLMR) and a slightly revised classification are presented. The number of known disorders has not increased because 6 disorders have been combined based on new molecular data or on clinical grounds and only 6 newly described XLMR disorders have been reported. Of the current 105 XLMR disorders, 34 have been mapped, and 18 disorders and 1 nonspecific XLMR (FRAXE) have been cloned. The number of families with nonspecific XLMR with a LOD score of > or = 2.0 has more than doubled, with 42 (including FRAXE) now being known. a summary of the localization of presumed nonspecific mental retardation (MR) genes from well-studied X-chromosomal translocations and deletions is also included. Only 10-12 nonoverlapping loci are required to explain all localizations of nonspecific MR from both approaches. These new trends mark the beginning of a significantly improved understanding of the role of genes on the X chromosome in producing MR. Continued close collaboration between clinical and molecular investigators will be required to complete the process.

Contrast sensitivity was determined for dyslexic and normal readers. When testing with temporally ramped (i.e. stimuli with gradual temporal onsets and offsets) gratings of 0.6, 4.0, and 12.0 cycles/deg, we found no difference in contrast sensitivity between dyslexic readers and controls. Using 12.0 cycles/deg gratings with transient (i.e. abrupt) onsets and offsets, we found that dyslexic individuals had, compared to controls, markedly inferior contrast sensitivity at the shortest stimulus durations (i.e. 17, 34, and 102 ms). This deficit may reflect more sluggish temporal summation. There was no difference in sensitivity to 0.6 cycles/deg gratings with transient onsets and offsets. Under these conditions, the two groups showed a consistent and equal increase in sensitivity relative to the ramped baseline condition at 0.6 cycles/deg at the longer stimulus durations. This demonstrates that dyslexic readers have no deficit in their ability to detect stimulus transients, a finding which appears to be inconsistent with a transient system deficit. That detection of the low-frequency stimuli was mediated by the transient system is further indicated by the fact that these stimuli were more susceptible to forward masking than were the high-frequency stimuli. The effects of masking of both high and low spatial-frequency stimuli were about equal for dyslexic readers and controls. This is not in agreement with the transient system deficit theory, according to which one would expect there to be less masking of high spatial-frequency stimuli in the case of dyslexic readers.

Aarskog-Scott syndrome was tentatively mapped to Xq13 on the basis of an X:8 translocation by Bawle et al. [Am J Med Genet 17:595-602, 1984]. A review of the cytogenetics and the use of molecular markers in that family have resulted in revision of the breakpoints of the translocation to Xp 11.2 and 8q11.21 [Glover et al., Hum Mol Genet 2:1717-1718, 1993]. Two families, including one of the two initial families with Aarskog-Scott syndrome [Scott, BD:OAS VII (6): 240-246, 1971], have participated in our study to evaluate the localization of the gene for Aarskog-Scott syndrome to the pericentromeric region of the X chromosome. Using a series of DNA probes, we have been able to confirm linkage to the X chromosome, with multipoint analysis indicating the most likely localization of the gene to be on the proximal short arm.

We provide a comprehensive list of all known forms of X-linked mental retardation. It comprises 127 entries, subdivided into 5 categories (syndromes, dominant disorders, metabolic disorders, neuromuscular disorders, and nonspecific mental retardation). Map location of 69 putative loci demonstrates several overlaps, which will only be resolved by more refined mapping or cloning of the respective genes. The ultimate goal of identifying all the genes on the X chromosome whose mutations cause mental retardation will require a concerted effort between clinical and molecular investigators.

In addition to providing information on the inheritance of dyslexia, the present study of eleven three-generation families has provided a unique opportunity to compare affected and unaffected family members at all ages. The data presented here are based on pedigree information, a questionnaire administered to all participating family members in relation to sex ratio, handedness, the severity of dyslexia by sex, pre- and perinatal complications, medical complications, years of education and earning ability, and a battery of standardized tests to define the presence or absence of dyslexia. The pattern of inheritance was consistent with the postulated autosomal dominant mode of inheritance and penetrance was found to be > 90 percent. Of 73 individuals determined to have a gene leading to dyslexia, seven were classified as obligate carriers and six as compensated adults who had no current symptoms or diagnostic evidence of dyslexia. The sex ratio (1.06) was not different from the expected ratio of 1.04. Left-handedness, major pre- and perinatal complications, and autoimmune disorders and allergy were not more common in dyslexics than non-dyslexics. The number of years of education and average income were similar in affected and unaffected family members. Compensated adults and obligate carriers were similar to unaffected family members in each of these parameters.

MASA syndrome includes mental retardation, adducted thumbs, shuffling gait and aphasia or speech delay. MASA syndrome, X-linked hydrocephalus and X-linked spastic paraplegia have been linked to the same markers on Xq28 and perhaps represent variation in the clinical expression of the same gene or manifestations of different mutant alleles. The present family includes five males in two generations with borderline to mild mental retardation (5/5), speech delay (5/5), spastic paraplegia (5/5), adducted thumbs (2/5) and marked hydrocephalus (1/5). Of these males, four were evaluated by MRI or CT scan and all four were determined to have partial to complete agenesis of the corpus callosum (ACC). DNA studies confirm linkage to Xq28 probe St14 (DXS52) with a lod score of 2.86 and no recombination. It is not known if X-linked ACC is linked to the same Xq28 region.

The accuracy of biochemical and molecular prenatal diagnoses using chorionic villi as the fetal source was assessed by seven centres participating in the NICHD collaborative study on the safety and accuracy of chorionic villus sampling (CVS) and amniocentesis. Of 601 pregnancies studied, biochemical methods were used to determine the diagnosis in 283 fetuses at risk for 35 different metabolic disorders. Fifteen different lysosomal storage diseases accounted for 81 per cent of the biochemical prenatal diagnoses performed, with 57 per cent of these pregnancies at risk for Tay-Sachs disease. No errors were made in the biochemical diagnoses that predicted affected or unaffected fetuses. However, the diagnoses of certain disorders (e.g., mucopolysacchariodosis type IH, metachromatic leukodystrophy, and Krabbe disease) occasionally required confirmatory studies in cultured amniocytes because the enzyme results were inconclusive in direct and/or cultured villi or due to the presence of a pseudodeficiency allele. Of these, only the diagnosis of a fetus at risk for Krabbe disease remained inconclusive after special studies to discriminate between mutant and pseudo-deficiency alleles. Recombinant DNA techniques were used to predict the diagnosis of 318 fetuses at risk for 16 different disorders in which the defective disease gene could be detected either directly or by linkage analysis to a nearby polymorphic marker. Of these, 32 per cent were for haemoglobinopathies, 25 per cent for cystic fibrosis, 24 per cent for Duchenne or Becker muscular dystrophy, and 7 per cent for haemophilias. Pregnancies at risk for known disorders with specific molecular lesions (e.g., sickle cell disease) were accurately diagnosed in direct and/or cultured villi. Diagnoses requiring analyses with closely linked polymorphic markers were occasionally uniformative or inconclusive. Maternal contamination was not reported in any biochemical or molecular-based diagnosis. These studies document the high accuracy and rapidity of both biochemical and mutation-specific prenatal diagnoses with direct and cultured chorionic villi.

Up to now, we have identified 77 X-linked conditions in which mental retardation is the primary or a major component manifestation. These conditions were subdivided into 2 categories, designated respectively "X-linked mental retardation syndromes" and "Non-specific X-linked mental retardation". Forty genes have been regionally mapped onto the X chromosome. However, in several instances the data were derived from a single family and most lod scores were less than 3.0.

A family in which 6 males have X-linked mental retardation has been studied with polymorphic DNA probes. The males differ from unaffected males only in impaired intellect and in smaller head size. The gene that causes mental retardation in the family appears to be located in band Xq21 on the basis of linkage with 3 markers: DXS250, DXS345 and DXS3 (theta max = 0.00; Zmax = 1.6). A multipoint lod score of 2.36 was obtain with no recombination relative to DXS326 in Xq21. This family is considered to have nonspecific X-linked mental retardation and has been given the designation MRX8.