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Abstract Background Pontocerebellar hypoplasia (PCH) is a heterogeneous group of diseases characterized by lack of development and/or early neurodegeneration of cerebellum and brainstem. According to clinical features, seven subtypes of PCH have been described, PCH type 2 related to TSEN54 mutations being the most frequent. PCH is most often autosomal recessive though de novo anomalies in the X-linked gene CASK have recently been identified in patients, mostly females, presenting with intellectual disability, microcephaly and PCH (MICPCH). Methods Fourteen patients (12 females and two males; aged 16 months-14 years) presenting with PCH at neuroimaging and with clinical characteristics unsuggestive of PCH1 or PCH2 were included. The CASK gene screening was performed using Array-CGH and sequencing. Clinical and neuroradiological features were collected. Results We observed a high frequency of patients with a CASK mutation (13/14). Ten patients (8 girls and 2 boys) had intragenic mutations and three female patients had a Xp11.4 submicroscopic deletion including the CASK gene. All were de novo mutations. Phenotype was variable in severity but highly similar among the 11 girls and was characterized by psychomotor retardation, severe intellectual disability, progressive microcephaly, dystonia, mild dysmorphism, and scoliosis. Other signs were frequently associated, such as growth retardation, ophthalmologic anomalies (glaucoma, megalocornea and optic atrophy), deafness and epilepsy. As expected in an X-linked disease manifesting mainly in females, the boy hemizygous for a splice mutation had a very severe phenotype with nearly no development and refractory epilepsy. We described a mild phenotype in a boy with a mosaic truncating mutation. We found some degree of correlation between severity of the vermis hypoplasia and clinical phenotype. Conclusion This study describes a new series of PCH female patients with CASK inactivating mutations and confirms that these patients have a recognizable although variable phenotype consisting of a specific form of pontocerebellar hypoplasia. In addition, we report the second male patient to present with a severe MICPCH phenotype and a de novo CASK mutation and describe for the first time a mildly affected male patient harboring a mosaic mutation. In our reference centre, CASK related PCH is the second most frequent cause of PCH. The identification of a de novo mutation in these patients enables accurate and reassuring genetic counselling.

Abstract Background Menkes Disease (MD) is a rare X-linked recessive fatal neurodegenerative disorder caused by mutations in the ATP7A gene, and most patients are males. Female carriers are mosaics of wild-type and mutant cells due to the random X inactivation, and they are rarely affected. In the largest cohort of MD patients reported so far which consists of 517 families we identified 9 neurologically affected carriers with normal karyotypes. Methods We investigated at-risk females for mutations in the ATP7A gene by sequencing or by multiplex ligation-dependent probe amplification (MLPA). We analyzed the X-inactivation pattern in affected female carriers, unaffected female carriers and non-carrier females as controls, using the human androgen-receptor gene methylation assay (HUMAR). Results The clinical symptoms of affected females are generally milder than those of affected boys with the same mutations. While a skewed inactivation of the X-chromosome which harbours the mutation was observed in 94% of 49 investigated unaffected carriers, a more varied pattern was observed in the affected carriers. Of 9 investigated affected females, preferential silencing of the normal X-chromosome was observed in 4, preferential X-inactivation of the mutant X chromosome in 2, an even X-inactivation pattern in 1, and an inconclusive pattern in 2. The X-inactivation pattern correlates with the degree of mental retardation in the affected females. Eighty-one percent of 32 investigated females in the control group had moderately skewed or an even X-inactivation pattern. Conclusion The X- inactivation pattern alone cannot be used to predict the phenotypic outcome in female carriers, as even those with skewed X-inactivation of the X-chromosome harbouring the mutation might have neurological symptoms.

Spinal muscular atrophy (SMA) is characterised by degeneration of anterior horn cells of the spinal cord and represents the second most common, lethal, autosomal recessive disorder after cystic fibrosis. Based on the criteria of the Internatinal SMA Consortium, childhood SMAs are classified into type I (Werdnig-Hoffmann disease), type II (intermediate form), and type III (Kugelberg-Welander disease). Recently, two genes have been found to be associated with SMA. The survival motor neurone gene (SMN) is an SMA determining gene as it is absent in 98.6% of patients. A second gene, XS2G3, or the highly homologous neuronal apoptosis inhibitory protein gene (NAIP) have been found to be more frequently deleted in type I than in the milder forms (types II and III). We investigated the correlation between the clinical phenotype and the genotype at this loci. A total of 106 patients were classified into type I (44), type II (31), and type III (31) and analysed using SMN, markers C212 and C272, and NAIP mapping upstream and downstream from SMN respectively. The combined analysis of all markers showed a large proportion of type I patients (43%) carried deletions of both SMN and its flanking markers (C212/272) and NAIP exon 5), as compared with none of the patients with type II or III SMA. The presence of large scale deletions involving these loci is specific to Werdnig-Hoffman disease (type I) and allows one to predict the severity of the disease in our series. [ABSTRACT FROM PUBLISHER]

Simpson-Golabi-Behmel syndrome (SGBS) is a rare X-linked multiple congenital abnormality/intellectual disability syndrome characterized by pre- and post-natal overgrowth, distinctive craniofacial features, macrocephaly, variable congenital malformations, organomegaly, increased risk of tumor and mild/moderate intellectual deficiency. In 1996, Glypican 3 (GPC3) was identified as the major gene causing SGBS but the mutation detection rate was only 28-70%, suggesting either genetic heterogeneity or that some patients could have alternative diagnoses. This was particularly suggested by some reports of atypical cases with more severe prognoses. In the family reported by Golabi and Rosen, a duplication of GPC4 was recently identified, suggesting that GPC4 could be the second gene for SGBS but no point mutations within GPC4 have yet been reported. In the genetics laboratory in Tours Hospital, GPC3 molecular testing over more than a decade has detected pathogenic mutations in only 8.7% of individuals with SGBS. In addition, GPC4 mutations have not been identified thus raising the question of frequent misdiagnosis. In order to better delineate the phenotypic spectrum of SGBS caused by GPC3 mutations, and to try to define specific clinical criteria for GPC3 molecular testing, we reviewed the clinical features of all male cases with a GPC3 mutation identified in the two molecular laboratories providing this test in France (Tours and Paris). We present here the results of the analysis of 42 patients belonging to 31 families and including five fetuses and three deceased neonates., (Copyright © 2013 Wiley Periodicals, Inc.)

Myoclonus dystonia (M-D) is a rare genetic movement disorder characterized by a combination of myoclonic jerks and dystonia. It is usually due to mutations in the SGCE gene. We report on a patient with a typical M-D syndrome, but also short stature, microcephaly, and mental retardation. Molecular analysis showed no mutations within the SGCE gene but a microdeletion encompassing the SGCE gene in chromosome region 7q21. Array-CGH analysis showed that the deletion spanned approximately 1.88 Mb. We suggest that M-D plus patients with mental retardation, microcephaly, dysmorphism, or short stature, all frequently associated disorders, should be screened for 7q21 microdeletion. By examining previously published cases of mental retardation associated with pure 7q21 deletions, we identified two distinct regions of respectively 455 and 496 kb that are critical for mental retardation and growth retardation. Among the genes located within these regions, LOC253012, also known as HEPACAM2, is a good candidate for both mental retardation and microcephaly., (Copyright 2010 Wiley-Liss, Inc.)

Sotos syndrome is an overgrowth syndrome characterized by distinctive facial features, learning difficulties, and macrocephaly with frequent pre- and postnatal overgrowth with advanced bone age. Here, we report on our experience in the molecular diagnostic of Sotos syndrome on 116 patients. Using direct sequencing and a quantitative multiplex PCR of short fluorescent fragments (QMPSF)-based assay allowing accurate detection of both total and partial NSD1 deletions, we identified NSD1 abnormalities in 104 patients corresponding to 102 Sotos families (90%). NSD1 point mutations were detected in 80% of the index cases, large deletions removing the NSD1 gene entirely in 14%, and intragenic NSD1 rearrangements in 6%. Among the 69 detected distinct point mutations, 48 were novel. The QMPSF assay detected an exonic duplication and a mosaic partial deletion. QMPSF mapping of the 15 large deletions revealed the heterogeneity of the deletions, which vary in size from 1 to 4.5 Mb. Clinical features of NSD1-positive Sotos patients revealed that the phenotype in patients with nontruncating mutations was less severe that in patients with truncating mutations. This study confirms the heterogeneity of NSD1 alterations in Sotos syndrome and therefore the need to complete sequencing analysis by screening for partial deletions and duplications to ensure an accurate molecular diagnosis of this syndrome., (2007 Wiley-Liss, Inc.)

Cleft lip with or without cleft palate (CL/P) is one of the most common congenital malformations in humans occurring with a birth prevalence of approximately 1:1,000. CL/P may be part of a defined syndrome, sequence or association, although most individual or familial cases present as an isolated (nonsyndromic) malformation (NSCL/P). Inheritance is generally regarded as multigenic although, in some families, NSCL/P seemingly segregates as a monogenic trait. On the other hand, van der Woude syndrome (vWS) is a rare autosomal dominant with cardinal features of lower-lip pits (LLP) and CL/P or cleft palate (alone). Since none of these traits is present in all mutation carriers, some individual or familial vWS cases, especially those lacking LLP, are indiscernible from NSCL/P, raising the question whether allelic variation at the vWS locus could underlie NSCL/P. This question was addressed using parametric linkage (LOD score) analysis in 21 multiplex NSCL/P families based on a tightly linked microsatellite marker (D1S3753), and nonparametric analysis using the transmission/disequilibrium test (GTDT) in 106 NSCL/P triads and selecting markers D1S205, D1S491, and D1S3753. No evidence for linkage of NSCL/P to vWS was found on the 21 families using the LOD score approach. In contrast, TDT yielded a significant P value of 0.04 for D1S205, supporting involvement of vWS in NSCL/P in a complex, modifying/polygenic manner rather than as a monogenic/major disease locus., (Copyright 2001 Wiley-Liss, Inc.)

Childhood spinal muscular atrophy (SMA) is a common recessive autosomal disorder that results in degeneration of lower motor neurons. The identification of the disease gene, Survival of Motor Neuron (SMN), was a major advance in understanding the molecular basis underlying this devastating neuromuscular disease. This finding has greatly improved the genetic counselling of SMA families. Recently, biochemical studies demonstrated its involvement in the biogenesis of spliceosomal snRNPs, suggesting a critical role of SMN in RNA processing. Surprisingly, other studies showed a putative role of SMN in an anti-apoptotic pathway involving Bcl-2. The function of SMN protein is not fully understood. These observations emphasized the difficulty in elucidating the function of any novel protein. Therefore, multidisciplinary approaches are required to understand the pathogenesis of SMA.

Mutations of the survival motor neurone gene (SMN) are associated with spinal muscular atrophy (SMA), a frequent lethal autosomal recessive disorder. In spite of this, no phenotype-genotype correlation was observed, since the SMN gene is lacking in the majority of patients affected with either the severe form (type I) or the milder forms (types II and III). Here, we show that the gene encoding p44, a subunit of the basal transcription factor TFIIH, is duplicated in the SMA region and that the p44 gene products (p44t and p44c) differ by three amino acid changes. Gene analysis of a total of 94 unrelated SMA patients revealed that the p44t gene is involved in large-scale deletions associated with Werdnig-Hoffmann disease (type I). The TFIIH polypeptide composition as well as transcription and DNA repair activities are normal in patients lacking the p44t gene on both mutant chromosomes, suggesting that the p44t gene is not critical for the development of SMA.

Spinal muscular atrophies (SMA) are characterized by degeneration of the anterior horn cells of the spinal cord and represent the second most common fatal autosomal-recessive disorder after cystic fibrosis. We have previously identified the survival motor neurone gene (SMN), a SMA-determining gene in the 5q13 region encoding a hitherto unknown protein. In this report, we describe the organization and structure of SMN. The gene is approximately equal to 20 kb in length and consists of nine exons. Sequence data of the 5' end of the gene show that the dinucleotide repeat C272 is close to several putative binding sites for transcription factors, which will help to characterize the regulation of the SMN and CBCD541 gene expression. The availability of the human SMN and its highly homologous counterpart (CBCD541) gene structures and exon-intron boundaries will hopefully speed up the characterization of SMN gene mutations in SMA.

Spinal muscular atrophy (SMA) is a frequent autosomal recessive disease characterized by degeneration of the motor neurons of the spinal cord causing proximal paralysis with muscle atrophy. The region on chromosome 5q13 encompassing the disease gene is particularly unstable and prone to large-scale deletions whose characterization recently led to the identification of the survival motor neuron (SMN) gene. We now present a genetic analysis of 54 unrelated Spanish SMA families that has revealed a 4-basepair (bp) deletion (AGAG) in exon 3 of SMN in four unrelated patients. This deletion, which results in a frameshift and a premature stop codon, occurs on the same haplotype background, suggesting that a single mutational event is involved in the four families. The other patients showed either deletions of the SMN gene (49/54) or a gene conversion event changing SMN exon 7 into its highly homologous copy (cBCD541, 1/54). This observation gives strong support to the view that mutations of the SMN gene are responsible for the SMA phenotype as it is the first frameshift mutation reported in SMA.

Spinal muscular atrophy (SMA) is a common fatal autosomal recessive disorder characterized by degeneration of lower motor neurons, leading to progressive paralysis with muscular atrophy. The gene for SMA has been mapped to chromosome 5q13, where large-scale deletions have been reported. We describe here the inverted duplication of a 500 kb element in normal chromosomes and narrow the critical region to 140 kb within the telomeric region. This interval contains a 20 kb gene encoding a novel protein of 294 amino acids. An highly homologous gene is present in the centromeric element of 95% of controls. The telomeric gene is either lacking or interrupted in 226 of 229 patients, and patients retaining this gene (3 of 229) carry either a point mutation (Y272C) or short deletions in the consensus splice sites of introns 6 and 7. These data suggest that this gene, termed the survival motor neuron (SMN) gene, is an SMA-determining gene.