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1.  Parkinson’s disease in GTP cyclohydrolase 1 mutation carriers 
Brain  2014;137(9):2480-2492.
Mutations in the gene encoding the dopamine-synthetic enzyme GTP cyclohydrolase-1 (GCH1) cause DOPA-responsive dystonia (DRD). Mencacci et al. demonstrate that GCH1 variants are associated with an increased risk of Parkinson's disease in both DRD pedigrees and in patients with Parkinson's disease but without a family history of DRD.
GTP cyclohydrolase 1, encoded by the GCH1 gene, is an essential enzyme for dopamine production in nigrostriatal cells. Loss-of-function mutations in GCH1 result in severe reduction of dopamine synthesis in nigrostriatal cells and are the most common cause of DOPA-responsive dystonia, a rare disease that classically presents in childhood with generalized dystonia and a dramatic long-lasting response to levodopa. We describe clinical, genetic and nigrostriatal dopaminergic imaging ([123I]N-ω-fluoropropyl-2β-carbomethoxy-3β-(4-iodophenyl) tropane single photon computed tomography) findings of four unrelated pedigrees with DOPA-responsive dystonia in which pathogenic GCH1 variants were identified in family members with adult-onset parkinsonism. Dopamine transporter imaging was abnormal in all parkinsonian patients, indicating Parkinson’s disease-like nigrostriatal dopaminergic denervation. We subsequently explored the possibility that pathogenic GCH1 variants could contribute to the risk of developing Parkinson’s disease, even in the absence of a family history for DOPA-responsive dystonia. The frequency of GCH1 variants was evaluated in whole-exome sequencing data of 1318 cases with Parkinson’s disease and 5935 control subjects. Combining cases and controls, we identified a total of 11 different heterozygous GCH1 variants, all at low frequency. This list includes four pathogenic variants previously associated with DOPA-responsive dystonia (Q110X, V204I, K224R and M230I) and seven of undetermined clinical relevance (Q110E, T112A, A120S, D134G, I154V, R198Q and G217V). The frequency of GCH1 variants was significantly higher (Fisher’s exact test P-value 0.0001) in cases (10/1318 = 0.75%) than in controls (6/5935 = 0.1%; odds ratio 7.5; 95% confidence interval 2.4–25.3). Our results show that rare GCH1 variants are associated with an increased risk for Parkinson’s disease. These findings expand the clinical and biological relevance of GTP cycloydrolase 1 deficiency, suggesting that it not only leads to biochemical striatal dopamine depletion and DOPA-responsive dystonia, but also predisposes to nigrostriatal cell loss. Further insight into GCH1-associated pathogenetic mechanisms will shed light on the role of dopamine metabolism in nigral degeneration and Parkinson’s disease.
doi:10.1093/brain/awu179
PMCID: PMC4132650  PMID: 24993959
GCH1; DOPA-responsive-dystonia; Parkinson’s disease; dopamine; exome sequencing
2.  High mutation detection rates in cerebral cavernous malformation upon stringent inclusion criteria: one-third of probands are minors 
Cerebral cavernous malformations (CCM) are prevalent vascular malformations occurring in familial autosomal dominantly inherited or isolated forms. Once CCM are diagnosed by magnetic resonance imaging, the indication for genetic testing requires either a positive family history of cavernous lesions or clinical symptoms such as chronic headaches, epilepsy, neurological deficits, and hemorrhagic stroke or the occurrence of multiple lesions in an isolated case. Following these inclusion criteria, the mutation detection rates in a consecutive series of 105 probands were 87% for familial and 57% for isolated cases. Thirty-one novel mutations were identified with a slight shift towards proportionally more CCM3 mutations carriers than previously published (CCM1: 60%, CCM2: 18%, CCM3: 22%). In-frame deletions and exonic missense variants requiring functional analyses to establish their pathogenicity were rare: An in-frame deletion within the C-terminal FERM domain of CCM1 resulted in decreased protein expression and impaired binding to the transmembrane protein heart of glass (HEG1). Notably, 20% of index cases carrying a CCM mutation were below age 10 and 33% below age 18 when referred for genetic testing. Since fulminant disease courses during the first years of life were observed in CCM1 and CCM3 mutation carriers, predictive testing of minor siblings became an issue.
doi:10.1002/mgg3.60
PMCID: PMC3960060  PMID: 24689081
Age at disease onset; CCM1; CCM2; CCM3; cerebral cavernous malformation; HEG1; mutation detection rate; predictive testing
3.  Rare Copy Number Variants Are a Common Cause of Short Stature 
PLoS Genetics  2013;9(3):e1003365.
Human growth has an estimated heritability of about 80%–90%. Nevertheless, the underlying cause of shortness of stature remains unknown in the majority of individuals. Genome-wide association studies (GWAS) showed that both common single nucleotide polymorphisms and copy number variants (CNVs) contribute to height variation under a polygenic model, although explaining only a small fraction of overall genetic variability in the general population. Under the hypothesis that severe forms of growth retardation might also be caused by major gene effects, we searched for rare CNVs in 200 families, 92 sporadic and 108 familial, with idiopathic short stature compared to 820 control individuals. Although similar in number, patients had overall significantly larger CNVs (p-value<1×10−7). In a gene-based analysis of all non-polymorphic CNVs>50 kb for gene function, tissue expression, and murine knock-out phenotypes, we identified 10 duplications and 10 deletions ranging in size from 109 kb to 14 Mb, of which 7 were de novo (p<0.03) and 13 inherited from the likewise affected parent but absent in controls. Patients with these likely disease causing 20 CNVs were smaller than the remaining group (p<0.01). Eleven (55%) of these CNVs either overlapped with known microaberration syndromes associated with short stature or contained GWAS loci for height. Haploinsufficiency (HI) score and further expression profiling suggested dosage sensitivity of major growth-related genes at these loci. Overall 10% of patients carried a disease-causing CNV indicating that, like in neurodevelopmental disorders, rare CNVs are a frequent cause of severe growth retardation.
Author Summary
With a frequency of 3%, shortness of stature is a common medical concern. Although family studies have clearly shown that gene defects play a pivotal role in the development of short stature, the underlying genetic variants involved remain unknown in about 80% of cases. In contrast to recent studies which aimed at the identification of common genetic variants to explain minor differences in the height variation in the general population, we targeted rare genomic variants where we expected a major gene effect on growth. By examining 200 patients clinically evaluated for short stature, we show that rare structural chromosomal aberrations (CNVs) are associated with shortness of stature in 10% of the cases. The identified CNVs were either de novo or segregated with short stature in the families and include genes that are functionally involved in growth regulation in humans or mice. We furthermore demonstrate an overlap of these CNVs with known microdeletion syndromes. Interestingly, 3 CNVs contain positions of common variants and confirm the localization of major growth-related genes. These findings are particularly important for identification of biological pathways leading to short stature, but also for further therapeutic approaches.
doi:10.1371/journal.pgen.1003365
PMCID: PMC3597495  PMID: 23516380
4.  Phenotypic variability of patients homozygous for the GJB2 mutation 35delG cannot be explained by the influence of one major modifier gene 
Hereditary hearing loss is a very heterogeneous trait, with 46 gene identifications for nonsyndromic hearing loss. Mutations in GJB2 cause up to half of all cases of severe-to-profound congenital autosomal recessive nonsyndromic hearing loss, with 35delG being the most frequent mutation in Caucasians. Although a genotype-phenotype correlation has been established for most GJB2 genotypes, the hearing loss of 35delG homozygous patients is mild-to-profound. We hypothesize that this phenotypic variability is at least partly caused by the influence of modifier genes. By performing a whole-genome association study on 35delG homozygotes, we sought to identify modifier genes. The association study was performed by comparing the genotypes of mild/moderate cases and profound cases. The first analysis included a pooling-based whole-genome association study of a first set of 255 samples by using both the Illumina 550K and Affymetrix 500K chips. This analysis resulted in a ranking of all analysed SNPs according to their p-values. The top 250 most significantly associated SNPs were genotyped individually in the same sample set. All 192 SNPs that still had significant p-values were genotyped in a second independent set of 297 samples for replication. The significant p-values were replicated in nine SNPs, with combined p-values between 3×10−3 and 1×10−4. This study suggests that the phenotypic variability in 35delG homozygous patients cannot be explained by the effect of one major modifier gene. Significantly associated SNPs may reflect a small modifying effect on the phenotype. Increasing the power of the study will be of the greatest importance to confirm these results.
doi:10.1038/ejhg.2008.201
PMCID: PMC2883287  PMID: 18985073
Hereditary hearing loss; connexin 26; 35delG; association study; modifier gene
5.  Phenotypic variability of patients homozygous for the GJB2 mutation 35delG cannot be explained by the influence of one major modifier gene 
Hereditary hearing loss (HL) is a very heterogeneous trait, with 46 gene identifications for non-syndromic HL. Mutations in GJB2 cause up to half of all cases of severe-to-profound congenital autosomal recessive non-syndromic HL, with 35delG being the most frequent mutation in Caucasians. Although a genotype–phenotype correlation has been established for most GJB2 genotypes, the HL of 35delG homozygous patients is mild to profound. We hypothesise that this phenotypic variability is at least partly caused by the influence of modifier genes. By performing a whole-genome association (WGA) study on 35delG homozygotes, we sought to identify modifier genes. The association study was performed by comparing the genotypes of mild/moderate cases and profound cases. The first analysis included a pooling-based WGA study of a first set of 255 samples by using both the Illumina 550K and Affymetrix 500K chips. This analysis resulted in a ranking of all analysed single-nucleotide polymorphisms (SNPs) according to their P-values. The top 250 most significantly associated SNPs were genotyped individually in the same sample set. All 192 SNPs that still had significant P-values were genotyped in a second independent set of 297 samples for replication. The significant P-values were replicated in nine SNPs, with combined P-values between 3 × 10−3 and 1 × 10−4. This study suggests that the phenotypic variability in 35delG homozygous patients cannot be explained by the effect of one major modifier gene. Significantly associated SNPs may reflect a small modifying effect on the phenotype. Increasing the power of the study will be of greatest importance to confirm these results.
doi:10.1038/ejhg.2008.201
PMCID: PMC2883287  PMID: 18985073
hereditary hearing loss; connexin 26; 35delG; association study; modifier gene
6.  Decreasing uptake of predictive testing for Huntington's disease in a German centre: 12 years' experience (1993–2004) 
In this retrospective study, we examined changes in decision-making for and against the predictive genetic test for Huntington's disease including 478 persons at risk who had undergone genetic counselling in one centre in Germany between 1993 and 2004. At the outset of the counselling procedure the majority of subjects (71%) wanted to make use of the test, yet the actual demand of the predictive test result declined from 67 to 38% over the years. In addition, the time interval between counselling session and blood withdrawal was reduced, as determined by the counselees: in 2000–2004 the majority of persons at risk made the appointment for blood withdrawal after the shortest possible time span. Demographic factors of the cohort remained comparatively stable in the investigated time period. An association was evident between the ratio of test usage and the counselling person. These and other possible factors influencing the time flow of predictive DNA testing are discussed. Further studies are necessary to investigate whether changes of test demand rates are a general phenomenon.
doi:10.1038/ejhg.2008.164
PMCID: PMC2986171  PMID: 18781186
genetic testing; genetic counselling; Huntington's disease; predictive testing
7.  HNPCC: Six new pathogenic mutations 
BMC Medical Genetics  2004;5:16.
Background
Hereditary non-polyposis colorectal cancer (HNPCC) is an autosomal dominant disease with a high risk for colorectal and endometrial cancer caused by germline mutations in DNA mismatch-repair genes (MMR). HNPCC accounts for approximately 2 to 5% of all colorectal cancers. Here we present 6 novel mutations in the DNA mismatch-repair genes MLH1, MSH2 and MSH6.
Methods
Patients with clinical diagnosis of HNPCC were counselled. Tumor specimen were analysed for microsatellite instability and immunohistochemistry for MLH1, MSH2 and MSH6 protein was performed. If one of these proteins was not detectable in the tumor mutation analysis of the corresponding gene was carried out.
Results
We identified 6 frameshift mutations (2 in MLH1, 3 in MSH2, 1 in MSH6) resulting in a premature stop: two mutations in MLH1 (c.2198_2199insAACA [p.N733fsX745], c.2076_2077delTG [p.G693fsX702]), three mutations in MSH2 (c.810_811delGT [p.C271fsX282], c.763_766delAGTGinsTT [p.F255fsX282], c.873_876delGACT [p.L292fsX298]) and one mutation in MSH6 (c.1421_1422dupTG [p.C475fsX480]). All six tumors tested for microsatellite instability showed high levels of microsatellite instability (MSI-H).
Conclusions
HNPCC in families with MSH6 germline mutations may show an age of onset that is comparable to this of patients with MLH1 and MSH2 mutations.
doi:10.1186/1471-2350-5-16
PMCID: PMC446196  PMID: 15217520
8.  The Nonfunctional Allele TCRBV6S1B Is Strongly Associated with Helicobacter pylori Infection 
Infection and Immunity  2000;68(11):6493-6495.
To determine genetic susceptibility factors for Helicobacter pylori infection, polymorphic T-cell receptor gene elements were investigated in 203 H. pylori-infected individuals and 180 uninfected individuals (controls). H. pylori infection is highly associated with individuals homozygous for the nonfunctional TCRBV6S1B element (odds ratio = 5.9; χ2 = 13; P = 0.00032; P value corrected for multiple comparisons [Bonferroni correction] = 0.00063).
PMCID: PMC97740  PMID: 11035766

Results 1-8 (8)