Bioscientia Center for Human Genetics

Ingelheim, Germany

Bioscientia Center for Human Genetics

Ingelheim, Germany
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Bergmann C.,Bioscientia Center for Human Genetics | Bergmann C.,Albert Ludwigs University of Freiburg
Cell and Tissue Research | Year: 2017

Most genetic disorders are clinically and genetically heterogeneous. Next-generation sequencing (NGS) has revolutionized the field and is providing rapidly growing insights into the pathomechanism of hereditary nephropathies. Current best-practice guidelines for most hereditary nephropathies include genetic diagnostics. The increasing number of genes that have to be considered in patients with hereditary nephropathies is often challenging when addressed by conventional techniques and largely benefits from NGS-based approaches that allow the parallel analysis of all disease genes in a single test at relatively low cost, e.g., by the use of multi-gene panels. Knowledge of the underlying genotype is of advantage in discussions with regard to transplantation and therapeutic options. Further, genetics may aid the early detection and treatment of renal and extrarenal complications and the reduction of invasive procedures. An accurate genetic diagnosis is crucial for genetic counselling, provides information about the recurrence risk and may help to improve the clinical management of patients and their families. The bottleneck in genetics is no longer the primary wet lab process but the interpretation of the obtained genetic data, which is by far the most challenging and work-intensive part of the analysis. This can only be managed in a multidisciplinary setting that brings together expert knowledge in genetics and the respective medical field. In the future, bench and bedside benefits can be expected from this kind of digitized medicine. © 2017, Springer-Verlag Berlin Heidelberg.

Ebermann I.,University of Cologne | Phillips J.B.,University of Oregon | Liebau M.C.,McGill University | Koenekoop R.K.,McGill University | And 19 more authors.
Journal of Clinical Investigation | Year: 2010

Usher syndrome is a genetically heterogeneous recessive disease characterized by hearing loss and retinitis pigmentosa (RP). It frequently presents with unexplained, often intrafamilial, variability of the visual phenotype. Although 9 genes have been linked with Usher syndrome, many patients do not have mutations in any of these genes, suggesting that there are still unidentified genes involved in the syndrome. Here, we have determined that mutations in PDZ domain-containing 7 (PDZD7), which encodes a homolog of proteins mutated in Usher syndrome subtype 1C (USH1C) and USH2D, contribute to Usher syndrome. Mutations in PDZD7 were identified only in patients with mutations in other known Usher genes. In a set of sisters, each with a homozygous mutation in USH2A, a frame-shift mutation in PDZD7 was present in the sister with more severe RP and earlier disease onset. Further, heterozygous PDZD7 mutations were present in patients with truncating mutations in USH2A, G protein-coupled receptor 98 (GPR98; also known as USH2C), and an unidentified locus. We validated the human genotypes using zebrafish, and our findings were consistent with digenic inheritance of PDZD7 and GPR98, and with PDZD7 as a retinal disease modifier in patients with USH2A. Pdzd7 knockdown produced an Usher-like phenotype in zebrafish, exacerbated retinal cell death in combination with ush2a or gpr98, and reduced Gpr98 localization in the region of the photoreceptor connecting cilium. Our data challenge the view of Usher syndrome as a traditional Mendelian disorder and support the reclassification of Usher syndrome as an oligogenic disease.

Khan A.O.,King Khaled Eye Specialist Hospital | Bergmann C.,Bioscientia Center for Human Genetics | Eisenberger T.,Bioscientia Center for Human Genetics | Bolz H.J.,Bioscientia Center for Human Genetics | And 2 more authors.
British Journal of Ophthalmology | Year: 2015

Background In Arabian children referred with retinal dystrophy, we have observed that a specific biallelic nonsense mutation in the gene encoding tubby-like protein 1 (TULP1, c.901C>T (p.Gln301∗)) is recurrent. This makes the mutation and its associated childhood retinopathy particularly interesting for genetic diagnostic and, potentially, gene therapy approaches. We characterise the ophthalmic phenotype associated with recessive p.Gln301∗ mutation in TULP1 and assess the mutation for single founder effect. Methods Retrospective consecutive case series (2011-2014) of 10 Arabian children (8 families) homozygous for the p.Gln301∗ mutation (detected after next-generation sequencing) and 12 ethnically matched controls. TULP1 haplotypes were constructed by analysis of TULP1 intragenic single nucleotide polymorphisms from next-generation sequencing data and genotyping of gene-flanking polymorphic microsatellite markers. Results All 10 children (2-8 years old; mean 5.2, median 6) had nystagmus since soon after birth, a grossly normal posterior pole other than arteriolar attenuation, peripheral mottling with apparent evolution to bone spicules, and hyperopia. Rod function was nonrecordable while cone function was present (albeit depressed and delayed); however, repeat electroretinogram years later in two children revealed loss of recordable cone function. Autofluorescence showed a hyper-fluorescent ring around the fovea while central optical coherence tomography was within normal limits. A specific haplotype was associated with p.Gln301∗ and was not present in controls. Conclusions The TULP1 allele p.Gln301∗ represents a founder mutation on the Arabian Peninsula and is associated with a recognisable congenital recessive rod-cone dystrophy phenotype in the homozygous state.

Elsayed S.M.,Medical Genetics Center | Elsayed S.M.,Ain Shams University | Heller R.,University of Cologne | Thoenes M.,University of Cologne | And 10 more authors.
European Journal of Human Genetics | Year: 2014

Although many genes have been identified for the autosomal recessive cerebellar ataxias (ARCAs), several patients are unlinked to the respective loci, suggesting further genetic heterogeneity. We combined homozygosity mapping and exome sequencing in a consanguineous Egyptian family with congenital ARCA, mental retardation and pyramidal signs. A homozygous 5-bp deletion in SPTBN2, the gene whose in-frame mutations cause autosomal dominant spinocerebellar ataxia type 5, was shown to segregate with ataxia in the family. Our findings are compatible with the concept of truncating SPTBN2 mutations acting recessively, which is supported by disease expression in homozygous, but not heterozygous, knockout mice, ataxia in Beagle dogs with a homozygous frameshift mutation and, very recently, a homozygous SPTBN2 nonsense mutation underlying infantile ataxia and psychomotor delay in a human family. As there was no evidence for mutations in 23 additional consanguineous families, SPTBN2-related ARCA is probably rare. © 2014 Macmillan Publishers Limited All rights reserved.

PubMed | University of Tübingen, Hamamatsu University School of Medicine, Childrens Hospital Krefeld, Max Delbrück Center for Molecular Medicine and 3 more.
Type: Journal Article | Journal: EMBO molecular medicine | Year: 2016

Mutations in the homeobox gene SHOX cause SHOX deficiency, a condition with clinical manifestations ranging from short stature without dysmorphic signs to severe mesomelic skeletal dysplasia. In rare cases, individuals with SHOX deficiency are asymptomatic. To elucidate the factors that modify disease severity/penetrance, we studied a three-generation family with SHOX deficiency. The variant p.Phe508Cys of the retinoic acid catabolizing enzyme CYP26C1 co-segregated with the SHOX variant p.Val161Ala in the affected individuals, while the SHOX mutant alone was present in asymptomatic individuals. Two further cases with SHOX deficiency and damaging CYP26C1 variants were identified in a cohort of 68 individuals with LWD The identified CYP26C1 variants affected its catabolic activity, leading to an increased level of retinoic acid. High levels of retinoic acid significantly decrease SHOX expression in human primary chondrocytes and zebrafish embryos. Individual morpholino knockdown of either gene shortens the pectoral fins, whereas depletion of both genes leads to a more severe phenotype. Together, our findings describe CYP26C1 as the first genetic modifier for SHOX deficiency.

PubMed | University of Bonn, University of Cologne, University of California at Los Angeles, University of Regensburg and 3 more.
Type: Journal Article | Journal: Investigative ophthalmology & visual science | Year: 2016

To investigate the effect of ABCA4 mutation status on lipofuscin-related quantitative autofluorescence (qAF) in humans and on bisretinoid accumulation in mice.Genotyped parents (n = 26; age 37-64 years) of patients with biallelic ABCA4-related retinopathy underwent in-depth retinal phenotyping including qAF imaging as a surrogate measure for RPE lipofuscin accumulation. In addition, bisretinoids as the main components of autofluorescent lipofuscin at the ocular fundus were quantified in Abca4-/-, Abca4+/-, and wild-type mice.Index patients showed a retinal phenotype characteristic for ABCA4-related retinopathy, including increased qAF levels. In contrast, qAF measures in carriers of only one ABCA4 mutation were not different from age-matched controls in this sample, and there was no difference between truncating and missense mutations. Also, none of these carriers presented an abnormal phenotype on conventional imaging. One parent with ABCA4-related retinopathy and increased qAF carried an additional ABCA4 mutation, explaining the phenotype under a recessive disease model (pseudodominance). Biochemical analysis in the mouse model revealed direct downstream products (A2PE-H2, at-RALdimer-PE) of the ABCA4 substrate N-Ret-PE to be similar in wild-type and Abca4+/- mice. Both bisretinoids were 12- to 18-fold increased in Abca4-/- mice. Levels of A2E and A2PE in Abca4+/- mice were in between those measured in wild-type and Abca4-/- mice.This study indicates that carriers of monoallelic ABCA4 mutations are phenotypically normal. However, biochemical analysis in the Abca4-deficient mouse model suggests detectable effects of one mutation in ABCA4 on the molecular level. The findings may have implications for therapeutic approaches such as gene replacement therapy.

Khan A.O.,King Khaled Eye Specialist Hospital | Al-Mesfer S.,King Khaled Eye Specialist Hospital | Al-Turkmani S.,King Khaled Eye Specialist Hospital | Bergmann C.,Bioscientia Center for Human Genetics | And 3 more authors.
British Journal of Ophthalmology | Year: 2014

Background Leber congenital amaurosis (LCA) is a severe infantile retinal dystrophy that is non-syndromic other than neurodevelopmental delay, reported in up to 20% of cases according to one older study. The phenotype is typically autosomal recessive and is genetically heterogeneous. Although LCA is defined by a non-recordable electroretinogram (ERG) during infancy, many LCA studies include infants with low ERG readings and/or older children not phenotyped during infancy. More recent series of genetically confirmed LCA do not document the recurrent neurodevelopmental delay of older studies. We investigate the possibility that neurodevelopmental delay is not actually a recurrent feature of strictly defined otherwise non-syndromic LCA.Methods Retrospective consecutive case series (2012-2014) of children with strictly defined LCA, all of whom underwent targeted next-generation sequencing with a panel of 14 LCA genes.Results All families were endogamous and/or consanguineous. 18/19 (22/23 children) had detectable causative recessive mutations, and these were in one of three genes only: 11 in RPGRIP1 , 5 in GUCY2D and 2 in RPE65. 9/11 children with RPGRIP1 mutations harboured homozygous c.1007delA ( p.Glu370Asnfs∗5) mutation. 5/23 children (22%) had concomitant neurodevelopmental delay, and these five children harboured recessive mutations in RPGRIP1 (2) or GUCY2D (3). Haplotype analysis for cases with the RPGRIP1 deletion suggested a single ancestral mutation.Conclusions Neurodevelopmental delay is a potential feature of strictly defined LCA, documented in our series for some children with homozygous RPGRIP1 and GUCY2D mutations. Strictly defining LCA can limit genetic heterogeneity. On the Arabian Peninsula, the phenotype is frequently from recessive RPGRIP1 mutations, most of which are a founder RPGRIP1 deletion.

Rabstein S.,Ruhr University Bochum | Harth V.,University of Hamburg | Justenhoven C.,Bioscientia Center for Human Genetics | Pesch B.,Ruhr University Bochum | And 9 more authors.
Chronobiology International | Year: 2014

Objectives: The role of genetic variants and environmental factors in breast cancer etiology has been intensively studied in the last decades. Gene-environment interactions are now increasingly being investigated to gain more insights into the development of breast cancer, specific subtypes, and therapeutics. Recently, night shift work that involves circadian disruption has gained rising interest as a potential non-genetic breast cancer risk factor. Here, we analyzed genetic polymorphisms in genes of cellular clocks, melatonin biosynthesis and signaling and their association with breast cancer as well as gene-gene and gene-night work interactions in a German case-control study on breast cancer. Methods: GENICA is a population-based case-control study on breast cancer conducted in the Greater Region of Bonn. Associations between seven polymorphisms in circadian genes (CLOCK, NPAS2, ARTNL, PER2 and CRY2), genes of melatonin biosynthesis and signaling (AANAT and MTNR1B) and breast cancer were analyzed with conditional logistic regression models, adjusted for potential confounders for 1022 cases and 1014 controls. Detailed shift-work information was documented for 857 breast cancer cases and 892 controls. Gene-gene and gene-shiftwork interactions were analyzed using model-based multifactor dimensionality reduction (mbMDR). Results: For combined heterozygotes and rare homozygotes a slightly elevated breast cancer risk was found for rs8150 in gene AANAT (OR 1.17; 95% CI 1.01-1.36), and a reduced risk for rs3816358 in gene ARNTL (OR 0.82; 95% CI 0.69-0.97) in the complete study population. In the subgroup of shift workers, rare homozygotes for rs10462028 in the CLOCK gene had an elevated risk of breast cancer (OR for AA vs. GG: 3.53; 95% CI 1.09-11.42). Shift work and CLOCK gene interactions were observed in the two-way interaction analysis. In addition, gene-shiftwork interactions were detected for MTNR1B with NPAS2 and ARNTL. Conclusions: In conclusion, the results of our population-based case-control study support a putative role of the CLOCK gene in the development of breast cancer in shift workers. In addition, higher order interaction analyses suggest a potential relevance of MTNR1B with the key transcriptional factor NPAS2 with ARNTL. Hence, in the context of circadian disruption, multivariable models should be preferred that consider a wide range of polymorphisms, e.g. that may influence chronotype or light sensitivity. The investigation of these interactions in larger studies is needed. © 2014 Informa Healthcare USA, Inc.

Striessnig J.,Institute of Pharmacy | Bolz H.J.,Bioscientia Center for Human Genetics | Bolz H.J.,University of Cologne | Koschak A.,Institute of Pharmacy
Pflugers Archiv European Journal of Physiology | Year: 2010

Voltage-gated Ca2+ channels couple membrane depolarization to Ca2+-dependent intracellular signaling events. This is achieved by mediating Ca2+ ion influx or by direct conformational coupling to intracellular Ca2+ release channels. The family of Cav1 channels, also termed L-type Ca2+ channels (LTCCs), is uniquely sensitive to organic Ca2+ channel blockers and expressed in many electrically excitable tissues. In this review, we summarize the role of LTCCs for human diseases caused by genetic Ca2+ channel defects (channelopathies). LTCC dysfunction can result from structural aberrations within their pore-forming α1 subunits causing hypokalemic periodic paralysis and malignant hyperthermia sensitivity (Cav1.1 α1), incomplete congenital stationary night blindness (CSNB2; Cav1.4 α1), and Timothy syndrome (Cav1.2 α1; reviewed separately in this issue). Cav1.3 α1 mutations have not been reported yet in humans, but channel loss of function would likely affect sinoatrial node function and hearing. Studies in mice revealed that LTCCs indirectly also contribute to neurological symptoms in Ca2+ channelopathies affecting non-LTCCs, such as Cav2.1 α1 in tottering mice. Ca 2+ channelopathies provide exciting disease-related molecular detail that led to important novel insight not only into disease pathophysiology but also to mechanisms of channel function. © The Author(s) 2010.

PubMed | Bioscientia Center for Human Genetics, University of Tübingen, Gemeinschaftspraxis fur Phoniatrie, University of Cologne and Gynakologie und Laboratoriumsmedizin
Type: | Journal: Clinical genetics | Year: 2016

In about 20% of non-syndromic hearing loss (NSHL) cases, inheritance is autosomal dominant (ADNSHL). DIAPH1 mutations define the ADNSHL locus DFNA1. We identified two new families with heterozygous truncating DIAPH1 mutations (p.Ala1210Serfs*31 and p.Arg1213*). In contrast to the extensively studied original DFNA1 family, hearing loss was not confined to low frequencies, but congenital manifestation and rapid progression were confirmed. In line with a recent unrelated study, we identified an association with thrombocytopenia, reclassifying DFNA1 as a syndrome. Consequently, we suggest to include the blood count into the initial clinical workup of patients with autosomal dominant hearing loss to guide the genetic diagnosis. We provide the first data on DIAPH1 expression in the organ of Corti, where it localizes to the inner pillar cells, at the base of the outer hair cells. Homozygous truncating DIAPH1 mutations located N-terminally to the DFNA1 mutations have recently been identified in autosomal recessive microcephaly. It is therefore noteworthy that we found DIAPH1 expression also in spiral ganglion neurons and in the barrier between the myelinating glia of the peripheral nervous system and oligodendrocytes that form the myelinating glia of the CNS.

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