1/36. Birth of healthy female twins after preimplantation genetic diagnosis of cystic fibrosis combined with gender determination. Two healthy sisters with a familial history of mental retardation were referred to our centre for preimplantation genetic diagnosis (PGD). Their two brothers showed severe mental retardation. The molecular basis for their disorder could not be identified, but one of the sisters and the mother presented a highly skewed pattern of X-inactivation reinforcing the likelihood of an X-linked mode of inheritance. Both sisters requested PGD to avoid the abortion of potentially affected male fetuses. PGD for sex by fluorescent in-situ hybridization was carried out for the first sister and resulted in the birth of a female child. The second sister and her partner, whose niece had cystic fibrosis (CF), were tested for CF mutations, and were both found to be deltaF508 heterozygous. We developed an efficient single cell PCR protocol for the simultaneous amplification of the CF (deltadeltaF508) locus as well as the X-linked amelogenin gene and its highly homologous pseudogene on the y chromosome. Two PGD cycles were carried out to screen against male and deltaF508 homozygous deleted embryos. In each case several embryos could be selected for transfer and the second cycle resulted in a twin pregnancy followed by the birth of two healthy female infants. ( info) |
2/36. Mental retardation and early onset of weakness in a girl with a dystrophinopathy and a large Xp21-23 deletion. A 2-year-old girl presented with severe global developmental delay weakness, and an elevated serum creatine kinase level. Her muscle biopsy was consistent with an active dystrophy with absence of dystrophin in about half of the muscle fibers. Fluorescent in situ hybridization analysis showed her karyotype to be 46, X, delX p23.1-p21.1. This large deletion includes the dystrophin gene as well as the region involved in X-linked mental retardation. The genetic mechanism for the manifestation of both diseases is likely non-random inactivation of the X chromosome. To our knowledge, the combination of this dystrophinopathy in association with severe mental retardation has not been described in a girl. ( info) |
3/36. Stocco dos Santos X-linked mental retardation syndrome: clinical elucidation and localization to Xp11.3-Xq21.3. 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. ( info) |
4/36. Inv(X)(p21.1;q22.1) in a man with mental retardation, short stature, general muscle wasting, and facial dysmorphism: clinical study and mutation analysis of the NXF5 gene. We describe a 59-year-old male (patient A059) with moderate to severe mental retardation (MR) and a pericentric inversion of the X-chromosome: inv(X)(p21.1;q22.1). He had short stature, pectus excavatum, general muscle wasting, and facial dysmorphism. Until now, no other patients with similar clinical features have been described in the literature. Molecular analysis of both breakpoints led to the identification of a novel "Nuclear rna export factor" (NXF) gene cluster on Xq22.1. Within this cluster, the NXF5 gene was interrupted with subsequent loss of gene expression. Hence, mutation analysis of the NXF5 and its neighboring homologue, the NXF2 gene was performed in 45 men with various forms of syndromic X-linked MR (XLMR) and in 70 patients with nonspecific XLMR. In the NXF5 gene four nucleotide changes: one intronic, two silent, and one missense (K23E), were identified. In the NXF2 gene two changes (one intronic and one silent) were found. Although none of these changes were causative mutations, we propose that NXF5 is a good candidate gene for this syndromic form of XLMR, given the suspected role of NXF proteins is within mRNA export/transport in neurons. Therefore, mutation screening of the NXF gene family in phenotypically identical patients is recommended. ( info) |
5/36. Oligophrenin 1 (OPHN1) gene mutation causes syndromic X-linked mental retardation with epilepsy, rostral ventricular enlargement and cerebellar hypoplasia. We identified an oligophrenin 1 (OPHN1) gene mutation in a family with five brothers affected by a recognizable pattern of clinical and neuroradiological hallmarks. The distinctive phenotype comprised moderate to severe mental retardation, myoclonic-astatic epilepsy, ataxia, strabismus and hypogenitalism. neuroimaging displayed fronto-temporal atrophy with rostral enlargement of the lateral ventricles, lower vermian agenesis and asymmetric cerebellar hypoplasia. mutation analysis of the OPHN1 gene on Xq12 disclosed a genomic deletion of exon 19 causing a frameshift. Notably, OPHN1 mutations have been previously reported as a rare cause of non-syndromic X-linked mental retardation. Our findings, however, indicate that OPHN1 mutations result in a recognizable syndrome. In addition, identification of OPHN1 as a further gene associated with epileptic seizures will help to unravel aetiologic factors of epilepsy. ( info) |
6/36. ARX mutations in X-linked lissencephaly with abnormal genitalia. X-linked lissencephaly with abnormal genitalia (XLAG) is a distinct form of lissencephaly associated with absent corpus callosum. Recently, forms of syndromic and nonspecific X-linked mental retardation have been found to be associated with mutations in the Aristaless-related homeobox gene ARX. The authors assessed ARX as a candidate gene for XLAG in a genetic analysis of neuronal migration disorders and found two different point mutations in two XLAG pedigrees affecting the homeodomain of the protein, confirming that ARX is a causative gene for XLAG. ( info) |
7/36. X-linked mild non-syndromic mental retardation with neuropsychiatric problems and the missense mutation A365E in PAK3. We describe a family of 19 males in five generations with mild to borderline non-syndromic X-linked mental retardation (MRX). There were no clinical manifestations in the affected males other than mental impairment and relatively long ears, with neuropsychiatric problems in some cases. Linkage analysis carried out on part of the pedigree using 34 markers spanning the X chromosome localized the gene between DXS454 and DXS1001 in Xq23. The maximum two-point lod score was 3.21 at DXS1059. PAK3 is a known MRX gene mapping to the same region. The affected males and obligate carrier females were found to have a missense mutation c.1094C > A in exon 10 causing an A365E substitution in a highly conserved region of the protein. The C to A base change abolishes a PvuII restriction enzyme site providing the basis for a simple test, if required, for carrier detection and prenatal diagnosis in the extended family. ( info) |
8/36. The proportion of cells with functional X disomy is associated with the severity of mental retardation in mosaic ring X turner syndrome females. turner syndrome females (45,X) do not have mental retardation (MR), whereas some mosaic ring X turner syndrome females, with 45,X/46,X,r(X), have severe MR. The MR is believed to be caused by a failure of x chromosome inactivation (XCI) of the small ring X chromosome, which leads to functional X disomy (FXD), To explore this hypothesis, we examined the proportion of FXD cells in the peripheral blood of four ring X turner syndrome females with various levels of MR, using two newly developed XCI assays based on dna methylation of X-linked genes. As a result, the two patients with extremely severe MR showed complete FXD patterns, whereas the remaining two patients with relatively milder MR showed partial FXD patterns. These results indicate that the proportion of FXD cells may be associated with the severity of MR in mosaic ring X turner syndrome females, although this association should be confirmed by examining brain cells during development. One of the cases with severe MR and a complete FXD pattern neither lacked the XIST gene nor had uniparental X isodisomy, and we discuss the mechanism of the failure of XCI in this case. ( info) |
9/36. Identification of two AGTR2 mutations in male patients with non-syndromic mental retardation. Mutations in the coding region of the angiotensin ii type 2 receptor gene (AGTR2) were recently identified to cause X-linked recessive mental retardation. We report a mutation screening of the AGTR2 gene in 57 Finnish male patients with non-syndromic mental retardation. We identified two mutations, a 62G-->T transversion, which leads to a substitution of glycine for valine (G21V) and a 157A-->T transversion, which causes a substitution of isoleucine for phenylalanine (I53F). The patients with AGTR2 sequence variants had severe/profound mental retardation, epileptic seizures, restlessness, hyperactivity, and disturbed development of speech. ( info) |
10/36. MECP2 gene mutations in non-syndromic X-linked mental retardation: phenotype-genotype correlation. Non-syndromic X-linked mental retardation (MRX) is a frequent cause of inherited mental retardation. It is a heterogeneous condition in which the first 12 genes discovered to date explain no more than 15% of the MRX situations ascertained by recurrence in multiplex families. In rett syndrome (RTT), an X-linked dominant condition mostly sporadic and usually lethal in males, most affected females have been shown to be mutated in the Methyl-CpG binding protein 2 gene (MECP2) that maps at Xq28. Some mentally retarded males related to RTT females carry the same mutation. Several MRX families mapping to Xq28 were subsequently tested for MECP2 and a causative mutation was discovered in three families, suggesting that it could be one of the main genes involved in MRX. We report here the corresponding phenotypes in these three families of increasing severity. In family 1, an in-frame deletion DeltaP387-M466 was found in the 3' region. The patients had severe to mild non-progressive MR, with better motor skills than verbal abilities. In family 2, an Arg to Trp substitution (R167W) was found between the transcription repression domain (TRD) and the methyl binding domain (MBD). The patients had brisk reflexes and essential tremor with mild and non-progressive MR, poor motor co-ordination and written language difficulties. In the third family (MRX16), a Glu to Gly substitution (E137G) was found in the MBD. The patients had manifestations similar to those of family 2, but MR was mild to moderate, speech articulation was poor and some had verbal stereotypies. Regression of language skills was suspected in three patients. phenotype-genotype correlation could thus be suspected and is discussed in these three families. ( info) |