SLC9A6 mutations cause X-linked mental retardation, microcephaly, epilepsy, and ataxia, a phenotype mimicking Angelman syndrome

Linkage analysis and DNA sequencing in a family exhibiting an X-linked mental retardation (XLMR) syndrome, characterized by microcephaly, epilepsy, ataxia, and absent speech and resembling Angelman syndrome, identified a deletion in the SLC9A6 gene encoding the Na(+)/H(+) exchanger NHE6. Subsequently, other mutations were found in a male with mental retardation (MR) who had been investigated for Angelman syndrome and in two XLMR families with epilepsy and ataxia, including the family designated as having Christianson syndrome. Therefore, mutations in SLC9A6 cause X-linked mental retardation. Additionally, males with findings suggestive of unexplained Angelman syndrome should be considered as potential candidates for SLC9A6 mutations.     

The clinical phenotype in institutionalised adult males with X-linked mental retardation (XLMR)

In an institutionalised population of 471 mentally retarded adult residents (436 males and 35 females), 22 males (i.e. 5 % of the male population) had XLMR, accounting for 36.1 % of the residents diagnosed with a monogenic disorder (n = 61). Fragile X syndrome (FRAXA) was diagnosed in 16 residents, X-linked mental retardation with marfanoid habitus (Lujan-Fryns syndrome) in 2, and non-specific X-linked mental retardation (MRX) in 4 males. The 4 MRX-patients included 3 male sibs of a family, carrying a mutation in the IL-1 receptor accessory protein-like gene, and one male patient member of the MRX-44 family (linkage with LOD-score of 2.90). In the group of 215 males with idiopathic mental retardation (MR), family histories and pedigree data were compatible with XLMR in 35 males (35/215 = 16.3 %) from 32 families. Of these 35 males, 5.7 % were microcephalic with dysmorphic features and 5.7 % macrocephalic; micro-orchidism and macro-orchidism were each found in 11.4 %. One macrocephalic male had also macro-orchidism and dysmorphic features. In this study, the diagnosis of XLMR could thus be proposed in 57 males i.e. 13.1 % of the total male population. The clinical phenotype, behavioural problems and follow-up data in these different subgroups of XLMR are presented.     

Renpenning syndrome maps to Xp11.

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.     

Mutations in the BRWD3 gene cause X-linked mental retardation associated with macrocephaly

In the course of systematic screening of the X-chromosome coding sequences in 250 families with nonsyndromic X-linked mental retardation (XLMR), two families were identified with truncating mutations in BRWD3, a gene encoding a bromodomain and WD-repeat domain–containing protein. In both families, the mutation segregates with the phenotype in affected males. Affected males have macrocephaly with a prominent forehead, large cupped ears, and mild-to-moderate intellectual disability. No truncating variants were found in 520 control X chromosomes. BRWD3 is therefore a new gene implicated in the etiology of XLMR associated with macrocephaly and may cause disease by altering intracellular signaling pathways affecting cellular proliferation.     

A novel X-linked recessive mental retardation syndrome comprising macrocephaly and ciliary dysfunction is allelic to oral–facial–digital type I syndrome

We report on a large family in which a novel X-linked recessive mental retardation (XLMR) syndrome comprising macrocephaly and ciliary dysfunction co-segregates with a frameshift mutation in the OFD1 gene. Mutations of OFD1 have been associated with oral–facial–digital type 1 syndrome (OFD1S) that is characterized by X-chromosomal dominant inheritance and lethality in males. In contrast, the carrier females of our family were clinically inconspicuous, and the affected males suffered from severe mental retardation, recurrent respiratory tract infections and macrocephaly. All but one of the affected males died from respiratory problems in infancy; and impaired ciliary motility was confirmed in the index patient by high-speed video microscopy examination of nasal epithelium. This family broadens the phenotypic spectrum of OFD1 mutations in an unexpected way and sheds light on the complexity of the underlying disease mechanisms.Electronic Supplementary Material Supplementary material is available to authorised users in the online version of this article at .     

Segregation of FRAXE in a large family: clinical, psychometric, cytogenetic, and molecular data.

During an ongoing study on X-linked mental retardation, we ascertained a large family in which mild mental retardation was cosegregating with a fragile site at Xq27-28. Clinical, psychometric, cytogenetic, and molecular studies were performed. Apart from mild mental retardation, affected males and females did not show a specific clinical phenotype. Psychometric assessment of four representative affected individuals revealed low academic achievements, with verbal and performance IQs of 61-75 and 70-82, respectively. Cytogenetically the fragile site was always present in affected males and was not always present in affected females. With FISH the fragile site was located within the FRAXE region. The expanded GCC repeat of FRAXE was seen in affected males and females either as a discrete band or as a broad smear. No expansion was seen in unaffected males, whereas three unaffected females did have an enlarged GCC repeat. Maternal transmission of FRAXE may lead to expansion or contraction of the GCC repeat length, whereas in all cases of paternal transmission contraction was seen. In striking contrast to the situation in fragile X syndrome, affected males may have affected daughters. In addition, there appears to be no premutation of the FRAXE GCC repeat, since in the family studied here all males lacking the normal allele were found to be affected.     

A novel dysmorphic syndrome with open calvarial sutures and sutural cataracts maps to chromosome 14q13-q21

We describe a new dysmorphic syndrome in an inbred Saudi Arabian family with 21 members. Five males and one female have similar craniofacial features including wide open calvarial sutures with large and late-closing anterior fontanels, frontal bossing, hyperpigmentation with capillary hemangioma of the forehead, significant hypertelorism, and a broad and prominent nose. In addition, these individuals have Y-shaped sutural cataracts diagnosed by 1-2 years of age. No chromosomal or biochemical abnormalities were identified. A genome-wide scan was performed, and two-point LOD score analysis, assuming autosomal recessive inheritance, detected linkage to chromosome 14q13-q21. The highest LOD scores were obtained for marker GATA136A04 (LOD=4.58 at theta=0.00) and for the adjacent telomeric marker D14S1048 (LOD=4.32 at theta=0.00). Multipoint linkage analysis resulted in a maximum LOD score of 5.44 between markers D14S1048 and GATA136A04. Model independent analysis by SIBPAL confirmed linkage to the same chromosomal region. Haplotype analysis indicated that all affected individuals were homozygous for the interval on chromosome 14q13-q21 with two recombinants for D14S1014 (centromeric) and one recombinant for D14S301 (telomeric). These recombinations limit the disease locus to a region of approximately 7.26 Mb. Candidate genes localized to this region were identified, and analysis of PAX9 did not identify mutations in these patients. The unique clinical phenotype and the mapping data suggest that this family represents a novel autosomal recessive syndrome.     

Monogenic causes of X-linked mental retardation

Mutations in X-linked genes are likely to account for the observation that more males than females are affected by mental retardation. Causative mutations have recently been identified in both syndromic X-linked mental retardation (XLMR) and in the genetically heterogeneous 'nonspecific' forms of XLMR, for which cognitive impairment is the only defining clinical feature. Proteins that function in chromatin remodelling are affected in three important syndromic forms of XLMR. In nonspecific forms of the disorder, defects have been found in signal-transduction pathways that are believed to function during neuronal maturation. These findings provide important insights into the molecular and cellular defects that underlie mental retardation.     

PPM-X: a new X-linked mental retardation syndrome with psychosis, pyramidal signs, and macroorchidism maps to Xq28.

We report a three-generation family manifesting a previously undescribed X-linked mental retardation syndrome. Four of the six moderately retarded males have had episodes of manic-depressive psychosis. The phenotype also includes pyramidal signs, Parkinsonian features, and macroorchidism, but there are no characteristic dysmorphic facial features. Affected males do not show fragile sites at distal Xq on cytogenetic analysis, nor do they have expansions of the CGG repeats at the FRAXA, FRAXE, or FRAXF loci. Linkage analyses were undertaken, and a maximal LOD score of 3.311 at theta = .0 was observed with the microsatellite marker DXS1123 in Xq28. A recombination was detected in one of the affected males with DXS1691 (Xq28), which gives the proximal boundary of the localization. No distal recombination has been detected at any of the loci tested.     

Mutations in ZDHHC9, which encodes a palmitoyltransferase of NRAS and HRAS, cause X-linked mental retardation associated with a Marfanoid habitus

We have identified one frameshift mutation, one splice-site mutation, and two missense mutations in highly conserved residues in ZDHHC9 at Xq26.1 in 4 of 250 families with X-linked mental retardation (XLMR). In three of the families, the mental retardation phenotype is associated with a Marfanoid habitus, although none of the affected individuals meets the Ghent criteria for Marfan syndrome. ZDHHC9 is a palmitoyltransferase that catalyzes the posttranslational modification of NRAS and HRAS. The degree of palmitoylation determines the temporal and spatial location of these proteins in the plasma membrane and Golgi complex. The finding of mutations in ZDHHC9 suggests that alterations in the concentrations and cellular distribution of target proteins are sufficient to cause disease. This is the first XLMR gene to be reported that encodes a posttranslational modification enzyme, palmitoyltransferase. Furthermore, now that the first palmitoyltransferase that causes mental retardation has been identified, defects in other palmitoylation transferases become good candidates for causing other mental retardation syndromes.     

Localization of a novel locus for alopecia with mental retardation syndrome to chromosome 3q26.33–q27.3

Alopecia with mental retardation syndrome is a rare autosomal recessive disorder characterized clinically by total or partial alopecia and mental retardation. In an effort to understand the molecular bases of this form of alopecia syndrome, large Pakistani consanguineous kindred with multiple affected individuals has been ascertained from a remote region in Pakistan. Genome wide scan mapped the disease locus on chromosome 3q26.33–q27.3. A maximum two-point LOD score of 3.05 (θ=0.0) was obtained at marker D3S3583. Maximum multipoint LOD score exceeding 5.0, obtained with several markers, supported the linkage. Recombination events observed in affected individuals localized the disease locus between markers D3S1232 and D3S2436, spanning 11.49-cM region on chromosome 3q26.33–q27.3. Sequence analysis of a candidate gene ETS variant gene 5 from DNA samples of two affected individuals of the family revealed no mutation.     

Disruptions of the novel KIAA1202 gene are associated with X-linked mental retardation

The extensive heterogeneity underlying the genetic component of mental retardation (MR) is the main cause for our limited understanding of the aetiology of this highly prevalent condition. Hence we set out to identify genes involved in MR. We investigated the breakpoints of two balanced X;autosome translocations in two unrelated female patients with mild/moderate MR and found that the Xp11.2 breakpoints disrupt the novel human KIAA1202 (hKIAA1202) gene in both cases. We also identified a missense exchange in this gene, segregating with the Stocco dos Santos XLMR syndrome in a large four-generation pedigree but absent in >1,000 control X-chromosomes. Among other phenotypic characteristics, the affected males in this family present with severe MR, delayed or no speech, seizures and hyperactivity. Molecular studies of hKIAA1202 determined its genomic organisation, its expression throughout the brain and the regulation of expression of its mouse homologue during development. Transient expression of the wild-type KIAA1202 protein in HeLa cells showed partial colocalisation with the F-actin based cytoskeleton. On the basis of its domain structure, we argue that hKIAA1202 is a new member of the APX/Shroom protein family. Members of this family contain a PDZ and two ASD domains of unknown function and have been shown to localise at the cytoskeleton, and play a role in neurulation, cellular architecture, actin remodelling and ion channel function. Our results suggest that hKIAA1202 may be important in cognitive function and/or development. Electronic Supplementary Material Supplementary material is available for this article at and is accessible for authorized users. O. Hagens and A. Dubos contributed equally to this work.     

FRAXA screening in Brazilian institutionalized individuals with nonspecific severe mental retardation

Individuals with mental disabilities are a heterogeneous group, mainly when we consider the etiology of mental retardation (MR). Recent advances in molecular genetics techniques have enabled us to unveil more about the molecular basis of several genetic syndromes associated with MR. In this study, we surveyed 85 institutionalized individuals with severe MR, 38 males and 47 females, by two molecular techniques, to detect CGG amplifications in the FMR1 gene. No FRAXA mutations were found in the FMR1 gene, reinforcing the low prevalence of Fragile X syndrome among institutionalized individuals with severe MR. We considered the PCR protocol used adequate for screening males with mental retardation of unknown etiology. The use of the Southern blot is still necessary for the decisive diagnosis of the Fragile X syndrome. To exclude chromosomal abnormalities associated with MR as a possible cause of the phenotype in these individuals, G-banded chromosome analysis was performed in all patients and 7.3% of chromosomal aberrations were found. Our results are similar to those reported previously and point to the necessity of expanding the molecular investigation toward other causes of MR, such as subtle chromosomal rearrangements, as suggested recent by a combination of fluorescence in situ hybridization (FISH) and PCR studies.     

Homozygosity mapping in families with Joubert syndrome identifies a locus on chromosome 9q34.3 and evidence for genetic heterogeneity

Joubert syndrome is a rare developmental defect of the cerebellar vermis, with autosomal recessive inheritance. The phenotype is highly variable and may include episodic hyperpnea, abnormal eye movements, hypotonia, ataxia, developmental delay, and mental retardation. Even within sibships the phenotype may vary, making it difficult to establish the exact clinical diagnostic boundaries of Joubert syndrome. To genetically localize the gene region, we have performed a whole-genome scan in two consanguineous families of Arabian/Iranian origins, with multiple affected probands. In one family, we detected linkage to the telomeric region of chromosome 9q, close to the marker D9S158, with a multipoint LOD score of Z=+3.7. The second family did not show linkage to this region, giving a first indication of genetic heterogeneity underlying Joubert syndrome. These findings were supported by subsequent analysis of two smaller families-one compatible with linkage to 9q; the other, unlinked. We conclude that Joubert syndrome is clinically and genetically heterogeneous and that one locus maps to chromosome 9q.     

X-linked mental retardation: many genes for a complex disorder

X-linked mental retardation (XLMR) is a common cause of moderate to severe intellectual disability in males. XLMR is very heterogeneous, and about two-thirds of patients have clinically indistinguishable non-syndromic (NS-XLMR) forms, which has greatly hampered their molecular elucidation. A few years ago, international consortia overcame this impasse by collecting DNA and cell lines from large cohorts of XLMR families, thereby paving the way for the systematic study of the molecular causes of XLMR. Mutations in known genes might already account for 50% of the families with NS-XLMR, and various genes have been pinpointed that seem to be of particular diagnostic importance. Eventually, even therapy of XLMR might become possible, as suggested by the unexpected plasticity of the neuronal wiring in the brain, and the recent successful drug treatment of a fly model for fragile X syndrome.     

Evidence that Smith-McCort dysplasia and Dyggve-Melchior-Clausen dysplasia are allelic disorders that result from mutations in a gene on chromosome 18q12

Smith-McCort dysplasia is a rare autosomal recessive osteochondrodysplasia characterized by short limbs and a short trunk with a barrel-shaped chest. The radiographic phenotype includes platyspondyly, generalized abnormalities of the epiphyses and metaphyses, and a distinctive lacy appearance of the iliac crest. We performed a genomewide scan in a consanguineous family from Guam and found evidence of linkage to loci on chromosome 18q12. Analysis of a second, smaller family was also consistent with linkage to this region, producing a maximum combined two-point LOD score of 3.04 at a recombination fraction of 0 for the marker at locus D18S450. A 10.7-cM region containing the disease gene was defined by recombination events in two affected individuals in the larger family. Furthermore, all affected children in the larger family were homozygous for a subset of marker loci within this region, defining a 1.5-cM interval likely to contain the defective gene. Analysis of three small, unrelated families with Dyggve-Melchior-Clausen syndrome, a radiographically identical disorder with the additional clinical finding of mental retardation, provided evidence of linkage to the same region, a result consistent with the hypothesis that the two disorders are allelic.     

MECP2 mutation in male patients with non-specific X-linked mental retardation

In contrast to the preponderance of affected males in families with X-linked mental retardation, Rett syndrome (RTT) is a neurological disorder occurring almost exclusively in females. The near complete absence of affected males in RTT families has been explained by the lethal effect of an X-linked gene mutation in hemizygous affected males. We report here on a novel mutation (A140V) in the MECP2 gene detected in one female with mild mental retardation. In a family study, the A140V mutation was found to segregate in the affected daughter and in four adult sons with severe mental retardation. These results indicate that MECP2 mutations are not necessarily lethal in males and that they can be causative of non-specific X-linked mental retardation.