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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.

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.

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.

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.

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.

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.

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.

One hundred normal caucasians were studied by sequential QFQ and RFA in order to estimate the type and frequency of variation. Colour variants were classified into 1 of 6 colours by RFA and intensity variations into 1 of 5 levels by QFQ. The interrelationship between QFQ and RFA variants was also examined. It was found that there was no consistent relationship between negative or brilliant QFQ variants and the various colours observed with RFA. RFA colour polymorphisms for chromosomes 13, 14, 15, 21 and 22 were 33.0, 38.0, 28.0, 50.0 and 24.5% while QFQ frequencies were 56.5, 10.0, 10.0, 15.5 and 10.0% respectively. RFA is especially useful in studying the inheritance of chromosome 21.

The possible effects of spray adhesives on human chromosomes were re-examined in several ways by three different laboratories. A total of 3,382 metaphases were analyzed in a blind-coded fashion. The proportion of abnormal cells, including gaps, was similar in both the control (8.2%) and exposed (8.3%) samples. Our findings do not confirm the original investigation in which the proportion of abnormal cells was found to be significantly higher in the exposed group (8.99%) than in the control group (1.65%). In the earlier study, however, blind-coded slides were not employed. These and other studies show no positive evidence of an effect of spray adhesives on human chromosomes.

We present a classification for secondary constriction (qh) regions with C-banding technique in chromosomes 1, 9, and 16 by means of comparing them to the short arm of chromosome 16. It is simple and convenient and can be used routinely. It can be incorporated into the modified Paris nomenclature system.

A reference diagram is presented which is comparable to the Paris banding diagram but which was based primarily on chromosomes studied by acridine orange reverse banding. Comparison with the Paris Conference (1971) banding diagram was made. Bands were combined in 13 instances and subdivided in 10 cases. The number of bands was found to depend primarily upon the length and quality of the chromosomes. No major differences between the present diagram and the Paris banding diagram were observed. Moreover, the results with acriding orange reverse banding were comparable to those previously reported with Giemsa R banding. In addition, sequential Q banding and R banding were carried out in the same cells. No significant differences in resolution of bands were observed when these two techniques were compared.

Long Y chromosomes is a relatively unbiased large sample of newborn infants were measured. The proportion of prior abortions was increased twofold in mothers of long Y infants compared to the control in the Caucasian sample. Our results indicate that an increased length of Y chromosome may be an important cause of fetal loss.

Sixty normal male Caucasians were selected to study the length of the Y chromosome. QFQ banding was performed. Chromosomes 19 and 20 (F) and Y were measured directly from the film. Y/F, f/F, and nf/F indices (f = fluorescent; nf = non-fluorescent segment) were determined. The length of the Y chromosome was classified into 5 groups; very small, small, average, large, and very large with Y/F indices of less than 0.8, 0.81--0.94, 0.95--1.09, 1.1--1.23, and greater than 1.23, respectively. The frequencies of Y/F indices for these groups were 0 (0%), 9 (15.0%), 40 (66.7%), 8 (13.3%), and 3 (5.0%), respectively. The most frequent class was 0.95--1.09 and was defined as the 'average' Y/F index for the human Y chromosome. The variation in the total length of the Y chromosome was accounted for by variations in the length of the non-fluorescent as well as the fluorescent segments. No relation between f and nf segments was observed. The mean Y/F, f/F, and nf/F indices were 1.022, 0.441, and 0.574, respectively.

Two children with the clinical features of Down syndrome were found to have several unusual cell lines. In both cases the same reverse tandem translocation between two 21 chromosomes was present in one line. This may be an unstable rearrangement. In addition, the findings offer some support for current efforts to localize the portion of chromosome 21 responsible for clinical features of Down syndrome to band 21q22. Acridine orange R banding was found to be especially useful in the identification of the break points on the translocations. The origin of the abnormality was found to be paternal in one case and was indeterminate in the second.

One hundred normal Caucasians were studied by the RFA technique to estimate the frequencies of size variation of the short arm of acrocentric chromosomes. Each size variation was classified into one of five levels. The most frequent size level(code) was 3; therefore, this was regarded as the 'average' size. If one excludes the average size, the frequencies of size variation by RFA for chromosome 13, 14, 15, 21, and 22 were 22.5, 19.5, 14.5, 19, and 17% respectively. There was no significant difference for the overall frequencies of size variation between sexes. Furthermore, the RFA technique detects more variation in the size of human acrocentric chromosomes than any other method.

We compared the spelling errors on the WRAT II made by adults (N = 24) with an apparent autosomal dominant form of dyslexia to those made by their normal adult relatives (N = 17) and by spelling-age matched normal controls (N = 17) using a computerized error evaluation program (SEEP). The normal adult relatives were significantly better than the dyslexics in both reading and spelling, but did not differ in age, education, or IQ. SEEP evaluated each error independently for both phonological and orthographic accuracy at 2 levels of complexity. Each level of complexity was analyzed separately using a 3 X 2 (group X dimension) analysis of variance. The main finding of interest was a significant group X dimension interaction effect at the complex level, which indicated that the dyslexics had a qualitatively different profile across the 2 dimensions than either normal group who had parallel profiles. The dyslexics performed like the younger normal group on the complex phonological dimension but like the adult normal group on the complex orthographic dimension. These results indicate a dissociation in this form of familial dyslexia between these 2 dimensions of spelling development, and suggest that these dyslexics may fit the subtype of dysphonetic or phonological dyslexia. The implications of these results for the underlying cognitive deficit in this form of dyslexia are discussed.

A simplified R banding technic is described which provides excellent delineation of major regions, easy identification of all chromosomes, and an accurate comparison of homologue lengths. The technic is simple, requiring only an initial incubation in buffer at 85 degrees C followed by acridine orange staining. The best presentation of the R banded chromosomes was obtained by printing in black and white from color transparency film. Variations in the length of the short arms of the acrocentric chromosomes are clearly and consistently defined. Satellites are not demarcated and appear as part of the short arm. Consistent banding was obtained, and the technic is suitable for use in routine clinical cytogenetic work.

Linkage analysis in families with apparent autosomal dominant reading disability produced a lod score of 3.241. Since the traditionally accepted significance level for linkage is a lod score of 3.0, these results strongly suggest that a gene playing a major etiologic role in one form of reading disability is on chromosome 15.

Significant linkage was found between spherocytosis and a translocation involving the short arms of chromosomes 8 and 12. The gene for spherocytosis, therefore, is likely either very close to the centromere of chromosome 8 or on 12p. The unusually high frequency of spontaneous abortion in this family was probably due to this translocation and was unrelated to the spherocytosis.

The incidence of gross chromosomal abnormality was measured in a large (4500), relatively unbiased sample of New Haven infants born during 1 year. The frequency of infants with abnormal chromosomal constitutions was 0.5 percent. For mothers over age 34, 1.5 percent of newborns were chromosomally abnormal. Only one in four of these infants could have been detected by phenotypic criteria alone. Methods are discussed whereby this fraction of the newborn population might be detected and possibly reduced.

In a survey of 860 unselected human placental extracts, three variants of mitochondrial glutamic oxaloacetic transaminase were found, all of which were common enough to be considered polymorphisms. Family studies showed that this enzyme is under the control of nuclear rather than mitochondrial DNA.

Differential staining of human chromosomes can be obtained when the pH of Giemsa stain is changed to 9.0 from the usual 6.8. Such staining permits identification of all homolog pairs and distinct regions within chromosome arms. In most instances, the pattern is quite similar to that obtained with quinacrine mustard fluorescence staining. Certain regions, such as the paracentric constrictions in chromosomes Al and C9, and the distal end of the long arm of the Y chromosome stain differently with the Giemsa 9 technique. The technique is considerably simpler than the quinacrine mustard fluorescence technique and identification of homologs is also easier than in cells stained by the latter.