Genetic and phenotypic characterization of NKX6-2-related spastic ataxia and hypomyelination.

BACKGROUND AND PURPOSE: Hypomyelinating leukodystrophies are a heterogeneous group of genetic disorders with a wide spectrum of phenotypes and a high rate of genetically unsolved cases. Bi-allelic mutations in NKX6-2 were recently linked to spastic ataxia 8 with hypomyelinating leukodystrophy. METHODS: Using a combination of homozygosity mapping, exome sequencing, and detailed clinical and neuroimaging assessment a series of new NKX6-2 mutations in a multicentre setting is described. Then, all reported NKX6-2 mutations and those identified in this study were combined and an in-depth analysis of NKX6-2-related disease spectrum was provided. RESULTS: Eleven new cases from eight families of different ethnic backgrounds carrying compound heterozygous and homozygous pathogenic variants in NKX6-2 were identified, evidencing a high NKX6-2 mutation burden in the hypomyelinating leukodystrophy disease spectrum. Our data reveal a phenotype spectrum with neonatal onset, global psychomotor delay and worse prognosis at the severe end and a childhood onset with mainly motor phenotype at the milder end. The phenotypic and neuroimaging expression in NKX6-2 is described and it is shown that phenotypes with epilepsy in the absence of overt hypomyelination and diffuse hypomyelination without seizures can occur. CONCLUSIONS: NKX6-2 mutations should be considered in patients with autosomal recessive, very early onset of nystagmus, cerebellar ataxia with hypotonia that rapidly progresses to spasticity, particularly when associated with neuroimaging signs of hypomyelination. Therefore, it is recommended that NXK6-2 should be included in hypomyelinating leukodystrophy and spastic ataxia diagnostic panels.

Disentangling the role of the tau gene locus in sporadic tauopathies.

Fibrillar aggregates of abnormally hyperphosphorylated tau protein are the major component of the pathological entities, including intraneuronal neurofibrillary tangles that define the broad class of late-onset neurodegenerative disorders called the tauopathies. Mutations in the tau gene (MAPT) causing familial frontotemporal dementia with parkinsonism linked to chromosome 17 (FTDP-17) confirm that tau protein dysfunction could be a primary cause of neuronal loss. However, in the sporadic tauopathies such as progressive supranuclear palsy (PSP) and corticobasal degeneration (CBD) where MAPT mutation is absent, common variation in MAPT that defines the H1 and H2 haplotype clades strongly influences disease risk. Surprisingly, this influence on risk extends to sporadic Parkinson's disease (PD), traditionally not defined as a tauopathy. This review will focus on recent work aimed at elucidating the mechanistic basis of this haplotype-specific effect on disease risk, implicating elevated levels of MAPT expression, particularly via increased transcription and/or alterations in splicing. This conforms to an emerging picture of a shared mechanism that underlies the fundamental process(es) leading to neuronal death. Increased availability of the fibrillogenic protein substrates of the pathological aggregates that define several neurodegenerative proteopathies, eg α-synuclein in PD, ß-amyloid in AD and tau in the tauopathies, contributes to causation and risk in the familial and sporadic forms of these disorders, respectively.

The heritability and genetics of frontotemporal lobar degeneration.

BACKGROUND: Frontotemporal lobar degeneration (FTLD) is a genetically and pathologically heterogeneous neurodegenerative disorder. METHODS: We collected blood samples from a cohort of 225 patients with a diagnosis within the FTLD spectrum and examined the heritability of FTLD by giving each patient a family history score, from 1 (a clear autosomal dominant history of FTLD) through to 4 (no family history of dementia). We also looked for mutations in each of the 5 disease-causing genes (MAPT, GRN, VCP, CHMP2B, and TARDP) and the FUS gene, known to cause motor neuron disease. RESULTS: A total of 41.8% of patients had some family history (score of 1, 2, 3, or 3.5), although only 10.2% had a clear autosomal dominant history (score of 1). Heritability varied across the different clinical subtypes of FTLD with the behavioral variant being the most heritable and frontotemporal dementia-motor neuron disease and the language syndromes (particularly semantic dementia) the least heritable. Mutations were found in MAPT (8.9% of the cohort) and GRN (8.4%) but not in any of the other genes. Of the remaining patients without mutations but with a strong family history, 7 had pathologic confirmation, falling into 2 groups: type 3 FTLD-TDP without GRN mutations (6) and FTLD-UPS (1). CONCLUSION: These findings show that frontotemporal lobar degeneration (FTLD) is a highly heritable disorder but heritability varies between the different syndromes. Furthermore, while MAPT and GRN mutations account for a substantial proportion of familial cases, there are other genes yet to be discovered, particularly in patients with type 3 FTLD-TDP without a GRN mutation.

TGFBR1 variants TGFBR1(*)6A and Int7G24A are not associated with an increased familial colorectal cancer risk.

Variants of the transforming growth factor-beta receptor type 1 (TGFBR1) gene, TGFBR1*6A and Int7G24A, have been suggested to act as low-penetrance tumour susceptibility alleles with TGFBR1*6A being causally responsible for some cases of familial colorectal cancer (CRC). We performed a case-control study of 262 unrelated familial CRC cases; 83 hereditary non-polyposis colorectal cancer (HNPCC) and 179 non-HNPCC. Patients were genotyped for TGFBR1*6A and Int7G24A and compared with 856 controls. Further, we screened the coding region of TGFBR1 in affected members of a large family with CRC linked to 9q22.32-31.1. TGFBR1*6A allelic frequency was not significantly different in all of the familial cases compared with controls (0.107 and 0.106, respectively; P=0.915). In a subgroup analysis allele frequencies were, however, different between HNPCC and non-HNPCC familial cases (0.157 and 0.084, respectively; P=0.013). TGFBR1*6A genotype did not influence age of onset. Int7G24A allele frequencies were similar in cases and controls. No germ-line mutation was identified in the family with CRC linked to this chromosomal region. Our study provides no substantial support for the hypothesis that the polymorphic variants TGFBR1*6A or Int7G24A contribute to familial CRC risk. We cannot, however, exclude the possibility that TGFBR1 variants have a modifying effect on inherited risk per se.

[Hereditary forms of colorectal adenomatous polyposis]. / Hereditární formy kolorektální adenomatózní polypózy.

BACKGROUND: Hereditary colorectal adenomatous polyposis syndromes are a predisposition to colorectal carcinoma development. The familial adenomatous polyposis is the most common analyzed syndrome that results from germline mutations in the APC gene. In addition to, the autosomal recessive form of polyposis has been recently reported. This disease is caused by germ-line mutations in the base excision repair MYH gene. The goal of this study is the identification of genetic causes of the colorectal polyposis, the determination of the frequency and type of the APC and MYH germ-line mutations in the set of families with colorectal polyposis in Czech population. METHODS AND RESULTS: The set of 103 probands with FAP was screened for germ-line APC mutations using the Protein Truncation Test and Denaturing Gradient Gel Electrophoresis. The MYH mutational screening was performed on 60 unrelated patients without detected APC mutations using the Denaturing High Performance Liquid Chromatography. Automated sequencing was carried out to identify found mutations. Totally, the 51 germ-line APC mutations (69,9%) are reported in the set of 72 probands including 31 novel mutations unique for Czech population. Molecular genetic analysis of the MYH gene revealed 15 DNA variations (25 %) including two patients identified as p.Y 165C/p.G382D compound heterozygotes (3,3%) and 13 polymorphisms or intronic changes (21,7%). The novel variants were detected in the 5 patients. CONCLUSION: Present study reflects the extremely heterogenous spectrum of the APC mutations in Czech population and confirms the previously reported data. However, the changes found in the MYH gene still need more extensive studies. Our results are important for genetic counselling and further clinical management among at-risk family members. It also enables distinction among different types of the colorectal polyposis.

Linkage analysis in a large Swedish family supports the presence of a susceptibility locus for adenoma and colorectal cancer on chromosome 9q22.32-31.1.

BACKGROUND: The best known hereditary colorectal cancer syndromes, familial adenomatous polyposis (FAP) and hereditary non-polyposis colorectal cancer (HNPCC), constitute about 2% of all colorectal cancers, and there are at least as many non-FAP, non-HNPCC cases where the family history suggests a dominantly inherited colorectal cancer risk. Recently, a locus on chromosome 9q22.2-31.2 was identified by linkage analysis in sib pairs with colorectal cancer or adenoma. METHODS: Linkage analysis for the suggested locus on chromosome 9 was carried out in an extended Swedish family. This family had previously been investigated but following the identification of adenomas in several previously unaffected family members, these subjects were now considered to be gene carriers. RESULTS: In the present study, we found linkage of adenoma and colorectal cancer to chromosome 9q22.32-31.1 with a multipoint LOD score of 2.4. We were also able to define the region for this locus to 7.9 cM between the markers D9S280 and D9S277. CONCLUSIONS: Our result supports the presence of a susceptibility locus predisposing to adenoma and colorectal cancer in this chromosomal region.

A genome wide linkage analysis in Swedish families with hereditary non-familial adenomatous polyposis/non-hereditary non-polyposis colorectal cancer.

BACKGROUND AND AIMS: Known colorectal cancer syndromes, such as familial adenomatous polyposis and hereditary non-polyposis colorectal cancer, have been identified in only a small proportion of cases with a family history of disease. In an attempt to identify loci harbouring novel predisposing genes, we have performed a genome wide linkage analysis in 18 colorectal cancer families recruited from the Department of Clinical Genetics at Karolinska Hospital, Sweden. METHODS: Multipoint parametric and non-parametric linkage analyses were performed using two affected status criteria, stringent and less stringent. Parametric analysis was performed under the assumption of locus homogeneity and locus heterogeneity. RESULTS: The initial scan performed using the less stringent affected status criteria revealed regions of interest on chromosome 11 (marker D11S1314: heterogeneity logarithm of odds (HLOD) score 1.96, non-parametric LOD (NPL) score 1.28; and marker D11S908: HLOD score 2.10, NPL score 2.16) and chromosome 14 (marker D14S258: HLOD score 2.61, NPL score 2.88). Using the stringent affected status criteria, a locus on chromosome 22 was suggested in the parametric analysis (marker D22S315: HLOD score 1.26). After finemapping of the regions on chromosomes 11 and 14, HLOD and NPL scores were reduced but still within the range of suggestive linkage. Haplotype analysis revealed overlapping regions between D11S987 and D11S4207 (proximal region), D11S4120 and D11S4090 (distal region), on chromosome 11, and between D14S1038 and D14S1069 on chromosome 14. CONCLUSION: Our study provides evidence of genetic heterogeneity among Swedish colorectal cancer families. Three novel regions were suggested to be of interest in a proportion of families analysed. Further studies are needed to confirm this result.

Molecular analysis of the APC and MYH genes in Czech families affected by FAP or multiple adenomas: 13 novel mutations.

Familial adenomatous polyposis (FAP) is an autosomal dominant predisposition to colorectal cancer and is caused by germline mutations in the adenomatous polyposis coli gene. The most prominent clinical manifestation is the presence of hundreds to thousands of colorectal polyps. A milder phenotype is found in patients affected with AFAP/ multiple adenomas. We screened the entire APC coding region using the combination of DGGE, PTT and direct sequencing and identified causative mutations in 52 of 77 patients. Thirteen of the mutations found were novel. In addition, we also tested 21 APC mutation/negative probands for the two most common mutations in the MYH gene. Four patients showed neither dominant transmission of the disease nor evidence of APC mutations. In one of them the most common biallelic germline mutation in the MYH gene was detected. Correlations between the localization of germline mutations and clinical manifestations of the diseases are discussed.