Publications by authors named "Jürgen Kohlhase"

102 Publications

EIF3F-related neurodevelopmental disorder: refining the phenotypic and expanding the molecular spectrum.

Orphanet J Rare Dis 2021 Mar 18;16(1):136. Epub 2021 Mar 18.

Institute of Human Genetics, Universitätsklinikum Erlangen, Friedrich-Alexander-Universität Erlangen-Nürnberg (FAU), Schwabachanlage 10, 91054, Erlangen, Germany.

Background: An identical homozygous missense variant in EIF3F, identified through a large-scale genome-wide sequencing approach, was reported as causative in nine individuals with a neurodevelopmental disorder, characterized by variable intellectual disability, epilepsy, behavioral problems and sensorineural hearing-loss. To refine the phenotypic and molecular spectrum of EIF3F-related neurodevelopmental disorder, we examined independent patients.

Results: 21 patients were homozygous and one compound heterozygous for c.694T>G/p.(Phe232Val) in EIF3F. Haplotype analyses in 15 families suggested that c.694T>G/p.(Phe232Val) was a founder variant. All affected individuals had developmental delays including delayed speech development. About half of the affected individuals had behavioral problems, altered muscular tone, hearing loss, and short stature. Moreover, this study suggests that microcephaly, reduced sensitivity to pain, cleft lip/palate, gastrointestinal symptoms and ophthalmological symptoms are part of the phenotypic spectrum. Minor dysmorphic features were observed, although neither the individuals' facial nor general appearance were obviously distinctive. Symptoms in the compound heterozygous individual with an additional truncating variant were at the severe end of the spectrum in regard to motor milestones, speech delay, organic problems and pre- and postnatal growth of body and head, suggesting some genotype-phenotype correlation.

Conclusions: Our study refines the phenotypic and expands the molecular spectrum of EIF3F-related syndromic neurodevelopmental disorder.
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http://dx.doi.org/10.1186/s13023-021-01744-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7977188PMC
March 2021

Cancer incidence and spectrum among children with genetically confirmed Beckwith-Wiedemann spectrum in Germany: a retrospective cohort study.

Br J Cancer 2020 08 26;123(4):619-623. Epub 2020 May 26.

Department of Pediatric Hematology and Oncology, Hannover Medical School, Carl-Neuberg-Str. 1, Hannover, 30625, Germany.

Background: Beckwith-Wiedemann syndrome (BWS) is a cancer predisposition syndrome caused by defects on chromosome 11p15.5. The quantitative cancer risks in BWS patients depend on the underlying (epi)genotype but have not yet been assessed in a population-based manner.

Methods: We identified a group of 321 individuals with a molecularly confirmed diagnosis of BWS and analysed the cancer incidence up to age 15 years and cancer spectrum by matching their data with the German Childhood Cancer Registry.

Results: We observed 13 cases of cancer in the entire BWS cohort vs 0.4 expected. This corresponds to a 33-fold increased risk (standardised incidence ratio (SIR) = 32.6; 95% confidence interval = 17.3-55.7). The specific cancers included hepatoblastoma (n = 6); nephroblastoma (n = 4); astrocytoma (n = 1); neuroblastoma (n = 1) and adrenocortical carcinoma (n = 1). The cancer SIR was highest in patients with a paternal uniparental disomy of 11p15.5 (UPDpat). A high cancer risk remained when cases of cancer diagnosed prior to the BWS diagnosis were excluded.

Conclusions: This study confirms an increased cancer risk in children with BWS. Our findings suggest that the highest cancer risk is associated with UPDpat. We were unable to confirm an excessive cancer risk in patients with IC1 gain of methylation (IC1-GOM) and this finding requires further investigation.
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http://dx.doi.org/10.1038/s41416-020-0911-xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7434760PMC
August 2020

Cerebellar Involvement in DYT-THAP1 Dystonia.

Cerebellum 2019 Oct;18(5):969-971

Department of Neurology, Medical Faculty, Heinrich Heine University Düsseldorf, Moorenstraße 5, 40225, Düsseldorf, Germany.

DYT-THAP1 dystonia is known to present a variety of clinical symptoms. To the best of our knowledge, this is the first case with DYT-THAP 1 dystonia and clinical signs of cerebellar involvement studied with transcranial magnetic stimulation in vivo. We report a case of a 51-year-old male DYT-THAP1 mutation carrier with dystonia, who additionally developed ataxia 1.5 years ago. To study cerebellar involvement in our patient, we used a TMS protocol called cerebellar inhibition (CBI). The lack of CBI in our patient strongly suggests cerebellar involvement. According to our findings, cerebellar syndrome may be part of the phenotypical spectrum of DYT-THAP1 mutations.
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http://dx.doi.org/10.1007/s12311-019-01062-0DOI Listing
October 2019

Multidisciplinary oral rehabilitation of an adolescent suffering from juvenile Gorlin-Goltz syndrome - a case report.

Head Face Med 2019 Feb 8;15(1). Epub 2019 Feb 8.

Department of Oral and Maxillofacial Surgery, University Hospital "Carl Gustav Carus", Technische Universität Dresden, Fetscherstr. 74, D-01307, Dresden, Germany.

Background: The Gorlin-Goltz syndrome is an autosomal dominant disorder characterized by keratocystic odontogenic tumors in the jaws, multiple basal cell carcinomas and skeletal abnormities. Frequently, the manifestation of the syndrome occurs in the adolescent years.

Case Presentation: An 11-year-old boy was referred to our clinic due to the persistence of the lower deciduous molars. The further diagnosis revealed bilateral keratocystic odontogenic tumors in the region of teeth 33 and 45 representing a symptom of a Gorlin-Goltz syndrome. This case of the oral rehabilitation of an adolescent with bilateral keratocystic odontogenic tumors shows the approach of a multidisciplinary treatment concept including the following elements: Enucleation and bone defect augmentation using a prefabricated bone graft; distraction osteogenesis to extend the graft-block vertically after cessation of growth; accompanying orthodontic treatment, guided implant placement and prosthetic rehabilitation. Six months after implant insertion, a new keratocystic odontogenic tumor in the basal part of the left sinus maxillaris had to be removed combined with the closure of the oroantral fistula. During the follow-up period of 18 months in semi-annual intervals, the patient showed no sign of pathology.

Conclusion: In the presented case could be shown that distraction osteogenesis of prefabricated bone blocks is possible. With a multidisciplinary approach in a long-term treatment a sufficient oral rehabilitation of the patient suffering from extended keratocystic odontogenic tumors was possible.
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http://dx.doi.org/10.1186/s13005-019-0189-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6367745PMC
February 2019

Functional characterization of a novel CSF1R mutation causing hereditary diffuse leukoencephalopathy with spheroids.

Mol Genet Genomic Med 2019 04 6;7(4):e00595. Epub 2019 Feb 6.

Institute of Human Genetics, Martin-Luther-University Halle-Wittenberg, Halle (Saale), Germany.

Background: Colony-stimulating factor 1 receptor is a tyrosine kinase transmembrane protein that mediates proliferation, differentiation, and survival of monocytes/macrophages and microglia. CSF1R gene mutations cause hereditary diffuse leukoencephalopathy with spheroids (HDLS), an autosomal-dominantly inherited microgliopathy, leading to early onset dementia with high lethality.

Methods: By interdisciplinary assessment of a complex neuropsychiatric condition in a 44-year old female patient, we narrowed down the genetic diagnostic to CSF1R gene sequencing. Flow cytometric analyses of uncultivated peripheral blood monocytes were conducted sequentially to measure the cell surface CSF1 receptor and autophosphorylation levels. Monocyte subpopulations were monitored during disease progression.

Results: We identified a novel heterozygous deletion-insertion mutation c.2527_2530delinsGGCA, p.(Ile843_Leu844delinsGlyIle) in our patient with initial signs of HDLS. Marginally elevated cell surface CSF1 receptor levels with increased Tyr723 autophosphorylation suggest an enhanced receptor activity. Furthermore, we observed a shift in monocyte subpopulations during disease course.

Conclusion: Our data indicate a mutation-related CSF1R gain-of-function, accompanied by an altered composition of the peripheral innate immune cells in our patient with HDLS. Since pharmacological targeting of CSF1R with tyrosine kinase inhibitors prevents disease progression in mouse models of neurodegenerative disorders, a potential pharmacological benefit of CSF1R inhibition remains to be elucidated for patients with HDLS.
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http://dx.doi.org/10.1002/mgg3.595DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6465730PMC
April 2019

Truncated SALL1 Impedes Primary Cilia Function in Townes-Brocks Syndrome.

Am J Hum Genet 2018 02;102(2):249-265

CIC bioGUNE, Bizkaia Technology Park, Building 801-A, 48160 Derio, Bizkaia, Spain. Electronic address:

Townes-Brocks syndrome (TBS) is characterized by a spectrum of malformations in the digits, ears, and kidneys. These anomalies overlap those seen in a growing number of ciliopathies, which are genetic syndromes linked to defects in the formation or function of the primary cilia. TBS is caused by mutations in the gene encoding the transcriptional repressor SALL1 and is associated with the presence of a truncated protein that localizes to the cytoplasm. Here, we provide evidence that SALL1 mutations might cause TBS by means beyond its transcriptional capacity. By using proximity proteomics, we show that truncated SALL1 interacts with factors related to cilia function, including the negative regulators of ciliogenesis CCP110 and CEP97. This most likely contributes to more frequent cilia formation in TBS-derived fibroblasts, as well as in a CRISPR/Cas9-generated model cell line and in TBS-modeled mouse embryonic fibroblasts, than in wild-type controls. Furthermore, TBS-like cells show changes in cilia length and disassembly rates in combination with aberrant SHH signaling transduction. These findings support the hypothesis that aberrations in primary cilia and SHH signaling are contributing factors in TBS phenotypes, representing a paradigm shift in understanding TBS etiology. These results open possibilities for the treatment of TBS.
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http://dx.doi.org/10.1016/j.ajhg.2017.12.017DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5985538PMC
February 2018

Large Deletions Targeting the Triple-Helical Domain of Collagen VII Lead to Mild Acral Dominant Dystrophic Epidermolysis Bullosa.

J Invest Dermatol 2018 04 24;138(4):987-991. Epub 2017 Nov 24.

Department of Dermatology, Medical Center-University of Freiburg, Faculty of Medicine, University of Freiburg, Germany. Electronic address:

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http://dx.doi.org/10.1016/j.jid.2017.11.014DOI Listing
April 2018

Hypomorphic mutations in POLR3A are a frequent cause of sporadic and recessive spastic ataxia.

Brain 2017 06;140(6):1561-1578

Center for Neurology and Hertie Institute for Clinical Brain Research, University of Tübingen, 72076 Tübingen, Germany.

Despite extensive efforts, half of patients with rare movement disorders such as hereditary spastic paraplegias and cerebellar ataxias remain genetically unexplained, implicating novel genes and unrecognized mutations in known genes. Non-coding DNA variants are suspected to account for a substantial part of undiscovered causes of rare diseases. Here we identified mutations located deep in introns of POLR3A to be a frequent cause of hereditary spastic paraplegia and cerebellar ataxia. First, whole-exome sequencing findings in a recessive spastic ataxia family turned our attention to intronic variants in POLR3A, a gene previously associated with hypomyelinating leukodystrophy type 7. Next, we screened a cohort of hereditary spastic paraplegia and cerebellar ataxia cases (n = 618) for mutations in POLR3A and identified compound heterozygous POLR3A mutations in ∼3.1% of index cases. Interestingly, >80% of POLR3A mutation carriers presented the same deep-intronic mutation (c.1909+22G>A), which activates a cryptic splice site in a tissue and stage of development-specific manner and leads to a novel distinct and uniform phenotype. The phenotype is characterized by adolescent-onset progressive spastic ataxia with frequent occurrence of tremor, involvement of the central sensory tracts and dental problems (hypodontia, early onset of severe and aggressive periodontal disease). Instead of the typical hypomyelination magnetic resonance imaging pattern associated with classical POLR3A mutations, cases carrying c.1909+22G>A demonstrated hyperintensities along the superior cerebellar peduncles. These hyperintensities may represent the structural correlate to the cerebellar symptoms observed in these patients. The associated c.1909+22G>A variant was significantly enriched in 1139 cases with spastic ataxia-related phenotypes as compared to unrelated neurological and non-neurological phenotypes and healthy controls (P = 1.3 × 10-4). In this study we demonstrate that (i) autosomal-recessive mutations in POLR3A are a frequent cause of hereditary spastic ataxias, accounting for about 3% of hitherto genetically unclassified autosomal recessive and sporadic cases; and (ii) hypomyelination is frequently absent in POLR3A-related syndromes, especially when intronic mutations are present, and thus can no longer be considered as the unifying feature of POLR3A disease. Furthermore, our results demonstrate that substantial progress in revealing the causes of Mendelian diseases can be made by exploring the non-coding sequences of the human genome.
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http://dx.doi.org/10.1093/brain/awx095DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6402316PMC
June 2017

Sustained Need for High-Dose Zinc Supplementation in Children With Acrodermatitis Enteropathica.

Clin Pediatr (Phila) 2018 01 5;57(1):99-102. Epub 2017 Jan 5.

1 University Hospital Erlangen, Erlangen, Germany.

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http://dx.doi.org/10.1177/0009922816685820DOI Listing
January 2018

FOXP2 variants in 14 individuals with developmental speech and language disorders broaden the mutational and clinical spectrum.

J Med Genet 2017 01 29;54(1):64-72. Epub 2016 Aug 29.

Institute of Human Genetics, Friedrich-Alexander-Universität Erlangen-Nürnberg (FAU), Erlangen, Germany.

Background: Disruptions of the FOXP2 gene, encoding a forkhead transcription factor, are the first known monogenic cause of a speech and language disorder. So far, mainly chromosomal rearrangements such as translocations or larger deletions affecting FOXP2 have been reported. Intragenic deletions or convincingly pathogenic point mutations in FOXP2 have up to date only been reported in three families. We thus aimed at a further characterisation of the mutational and clinical spectrum.

Methods: Chromosomal microarray testing, trio exome sequencing, multigene panel sequencing and targeted sequencing of FOXP2 were performed in individuals with variable developmental disorders, and speech and language deficits.

Results: We identified four different truncating mutations, two novel missense mutations within the forkhead domain and an intragenic deletion in FOXP2 in 14 individuals from eight unrelated families. Mutations occurred de novo in four families and were inherited from an affected parent in the other four. All index patients presented with various manifestations of language and speech impairment. Apart from two individuals with normal onset of speech, age of first words was between 4 and 7 years. Articulation difficulties such as slurred speech, dyspraxia, stuttering and poor pronunciation were frequently noted. Motor development was normal or only mildly delayed. Mild cognitive impairment was reported for most individuals.

Conclusions: By identifying intragenic deletions or mutations in 14 individuals from eight unrelated families with variable developmental delay/cognitive impairment and speech and language deficits, we considerably broaden the mutational and clinical spectrum associated with aberrations in FOXP2.
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http://dx.doi.org/10.1136/jmedgenet-2016-104094DOI Listing
January 2017

Failure of ossification of the occipital bone in mandibuloacral dysplasia type B.

Am J Med Genet A 2016 10 13;170(10):2750-5. Epub 2016 Jul 13.

Department of Genetics, APHP-Robert Debré University Hospital and Paris VII-Denis Diderot Medical School Paris, Paris, France.

Mandibuloacral dysplasia with type B lipodystrophy is a rare autosomal recessive disease characterized by atrophic skin, lipodystrophy, and skeletal features. It is caused by mutations in ZMPSTE24, a gene encoding a zinc metalloproteinase involved in the post-translational modification of lamin. Nine distinct pathogenic variants have been identified in 11 patients from nine unrelated families with this disorder. We report a 12-year-old boy with mandibuloacral dysplasia with type B lipodystrophy and a novel homozygous c.1196A>G; p.(Tyr399Cys) mutation in ZMPSTE24. The patient had typical dermatological and skeletal features of mandibuloacral dysplasia with type B lipodystrophy, sparse hair, short stature, mild microcephaly, facial dysmorphism, and a striking failure of ossification of the interparietal region of the occipital bone, up to the position where transverse occipital suture can be observed. Newly recognized signs for mandibuloacral dysplasia with type B lipodystrophy were gaze palsy and ptosis. Delayed closure of cranial sutures and Wormian bones have been described in three patients, but an ossification failure strictly limited to the occipital bone, as seen in the present patient, appears to be unique for mandibuloacral dysplasia with type B lipodystrophy. This observation illustrates that ZMPSTE24 could play a specific role in membranous ossification in the interparietal part of the squama (Inca bone) but not in the intracartilaginous ossification of the supraoccipital. This failure of ossification in the squama appears to be a useful feature for the radiological diagnosis of mandibuloacral dysplasia with type B lipodystrophy. © 2016 Wiley Periodicals, Inc.
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http://dx.doi.org/10.1002/ajmg.a.37825DOI Listing
October 2016

A Novel ECM1 Splice Site Mutation in Lipoid Proteinosis: Case Report plus Review of the Literature.

Mol Syndromol 2016 Apr 15;7(1):26-31. Epub 2016 Mar 15.

Departments of Human Genetics, University Witten/Herdecke, Witten, Germany; Departments of Center for Rare Diseases Ruhr (CeSER), Bochum, Germany.

Lipoid proteinosis (LP) is an autosomal recessive genodermatosis known to be caused by mutations in ECM1. Nonsense and missense mutations are the most common variations in LP. Up to date, only 6 splice site mutations have been observed. We report on a 26-year-old female LP patient from a Turkish consanguineous family carrying a novel homozygous splice site mutation in intron 8 of the ECM1 gene and summarize the current knowledge on ECM1 mutations and possible genotype-phenotype correlations.
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http://dx.doi.org/10.1159/000444615DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4862396PMC
April 2016

Identification of a Novel Point Mutation in the LEMD3 Gene in an Infant With Buschke-Ollendorff Syndrome.

JAMA Dermatol 2016 07;152(7):844-5

Department of Dermatology, Venerology, and Allergology, University of Leipzig, Leipzig, Germany.

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http://dx.doi.org/10.1001/jamadermatol.2016.0350DOI Listing
July 2016

Single Amino Acid Deletion in Kindlin-1 Results in Partial Protein Degradation Which Can Be Rescued by Chaperone Treatment.

J Invest Dermatol 2016 05 28;136(5):920-929. Epub 2016 Jan 28.

Department of Dermatology, Medical Center, University of Freiburg, Freiburg, Germany. Electronic address:

Kindler syndrome, a distinct type of epidermolysis bullosa, is a rare disorder caused by mutations in FERMT1, encoding kindlin-1. Most FERMT1 mutations lead to premature termination codons and absence of kindlin-1. Here we investigated the molecular and cellular consequences of a naturally occurring FERMT1 mutation, c.299_301del resulting in a single amino acid deletion, p.R100del. The mutation led to a 50% reduction of FERMT1 mRNA and 90% reduction of kindlin-1 protein in keratinocytes derived from the patient, as compared with control cells. The misfolded p.R100del kindlin-1 mutant was lysosomally degraded and launched a homeostatic unfolded protein response. Sodium-phenylbutyrate significantly increased kindlin-1 mRNA and protein levels and the area of mutant cells, acting as a chemical chaperone and probably also as a histone deacetylase inhibitor. In a recombinant system, low levels of wild-type or p.R100del mutant kindlin-1 were sufficient to improve the cellular phenotype in respect of spreading and proliferation as compared with kindlin-1 negative keratinocytes. The study of this hypomorphic mutation provides evidence that low amounts of kindlin-1 are sufficient to improve the epidermal architecture and Kindler syndrome cellular phenotype and proposes a personalized chaperone therapy for the patient.
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http://dx.doi.org/10.1016/j.jid.2015.12.039DOI Listing
May 2016

DICER1 syndrome can mimic different genetic tumor predispositions.

Cancer Lett 2016 Jan 11;370(2):275-8. Epub 2015 Nov 11.

Institute of Human Genetics, University Hospital, University of Munich, Munich, Germany. Electronic address:

DICER1, a RNAse endonuclease involved in the processing of siRNA and microRNA, is known to play a pivotal role in the post-transcriptional regulation of gene expression. Germ line mutations in the DICER1 gene increase the risk for different types of tumors. At present, DICER1 syndrome is an established, though not well defined, member of the group of genetic tumor predisposition syndromes. Here, we report a DICER1 syndrome family with a medical history of different rare tumors mostly occurring at a young age. The tumor spectrum in this family included both DICER1 syndrome-typical forms, such as pleuropulmonary blastoma, multinodular goiter, and cystic nephroma, and not previously reported manifestations, such as pilomatrixoma, and juvenile basal cell carcinoma. The latter tumor types are usually considered to be indicators of familial adenomatous polyposis and basal cell nevus syndrome.
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http://dx.doi.org/10.1016/j.canlet.2015.11.002DOI Listing
January 2016

A Deep-Intronic FERMT1 Mutation Causes Kindler Syndrome: An Explanation for Genetically Unsolved Cases.

J Invest Dermatol 2015 Nov 17;135(11):2876-2879. Epub 2015 Jun 17.

Department of Dermatology, Medical Center-University of Freiburg, Freiburg, Germany. Electronic address:

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http://dx.doi.org/10.1038/jid.2015.227DOI Listing
November 2015

New mutation leading to the full variety of typical features of the Netherton syndrome.

J Dtsch Dermatol Ges 2015 Jul 30;13(7):691-3. Epub 2015 May 30.

Department of Dermatology, University of Heidelberg, Ruprecht-Karls-University Heidelberg, Germany.

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http://dx.doi.org/10.1111/ddg.12453DOI Listing
July 2015

Stüve-Wiedemann syndrome in a neonate.

Pediatr Int 2015 Apr;57(2):302-4

1st Department of Neonatology, Aristotle University of Thessaloniki, Thessaloniki, Greece.

We describe a female neonate with Stüve-Wiedemann syndrome. The facial dysmorphism, joint contracture, distinctive skeletal changes, and myotonic discharges on electromyogram raised a suspicion of the rare autosomal recessive syndrome, which was later confirmed on molecular analysis of leukemia inhibitory factor receptor. She developed recurrent attacks of hyperpyrexia and died at age 3 months.
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http://dx.doi.org/10.1111/ped.12431DOI Listing
April 2015

Pilomatricomas in Rubinstein-Taybi syndrome.

J Dtsch Dermatol Ges 2015 Mar;13(3):240-2

Department of Dermatology and Venereology, Otto-von-Guericke University, Magdeburg, Germany.

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http://dx.doi.org/10.1111/ddg.12504DOI Listing
March 2015

Next-generation sequencing in X-linked intellectual disability.

Eur J Hum Genet 2015 Nov 4;23(11):1513-8. Epub 2015 Feb 4.

Institute of Medical Genetics and Applied Genomics, University of Tübingen, Tübingen, Germany.

X-linked intellectual disability (XLID) is a genetically heterogeneous disorder with more than 100 genes known to date. Most genes are responsible for a small proportion of patients only, which has hitherto hampered the systematic screening of large patient cohorts. We performed targeted enrichment and next-generation sequencing of 107 XLID genes in a cohort of 150 male patients. Hundred patients had sporadic intellectual disability, and 50 patients had a family history suggestive of XLID. We also analysed a sporadic female patient with severe ID and epilepsy because she had strongly skewed X-inactivation. Target enrichment and high parallel sequencing allowed a diagnostic coverage of >10 reads for ~96% of all coding bases of the XLID genes at a mean coverage of 124 reads. We found 18 pathogenic variants in 13 XLID genes (AP1S2, ATRX, CUL4B, DLG3, IQSEC2, KDM5C, MED12, OPHN1, SLC9A6, SMC1A, UBE2A, UPF3B and ZDHHC9) among the 150 male patients. Thirteen pathogenic variants were present in the group of 50 familial patients (26%), and 5 pathogenic variants among the 100 sporadic patients (5%). Systematic gene dosage analysis for low coverage exons detected one pathogenic hemizygous deletion. An IQSEC2 nonsense variant was detected in the female ID patient, providing further evidence for a role of this gene in encephalopathy in females. Skewed X-inactivation was more frequently observed in mothers with pathogenic variants compared with those without known X-linked defects. The mutation rate in the cohort of sporadic patients corroborates previous estimates of 5-10% for X-chromosomal defects in male ID patients.
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http://dx.doi.org/10.1038/ejhg.2015.5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4613482PMC
November 2015

Further delineation of the KAT6B molecular and phenotypic spectrum.

Eur J Hum Genet 2015 Sep 26;23(9):1165-70. Epub 2014 Nov 26.

Manchester Centre For Genomic Medicine, University of Manchester, St Mary's Hospital, Manchester Academic Health Science Centre, Manchester, UK.

KAT6B sequence variants have been identified previously in both patients with the Say-Barber-Biesecker type of blepharophimosis mental retardation syndromes (SBBS) and in the more severe genitopatellar syndrome (GPS). We report on the findings in a previously unreported group of 57 individuals with suggestive features of SBBS or GPS. Likely causative variants have been identified in 34/57 patients and were commonly located in the terminal exons of KAT6B. Of those where parental samples could be tested, all occurred de novo. Thirty out of thirty-four had truncating variants, one had a missense variant and the remaining three had the same synonymous change predicted to affect splicing. Variants in GPS tended to occur more proximally to those in SBBS patients, and genotype/phenotype analysis demonstrated significant clinical overlap between SBBS and GPS. The de novo synonymous change seen in three patients with features of SBBS occurred more proximally in exon 16. Statistical analysis of clinical features demonstrated that KAT6B variant-positive patients were more likely to display hypotonia, feeding difficulties, long thumbs/great toes and dental, thyroid and patella abnormalities than KAT6B variant-negative patients. The few reported patients with KAT6B haploinsufficiency had a much milder phenotype, though with some features overlapping those of SBBS. We report the findings in a previously unreported patient with a deletion of the KAT6B gene to further delineate the haploinsufficiency phenotype. The molecular mechanisms giving rise to the SBBS and GPS phenotypes are discussed.
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http://dx.doi.org/10.1038/ejhg.2014.248DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4351891PMC
September 2015

CHD7, the gene mutated in CHARGE syndrome, regulates genes involved in neural crest cell guidance.

Hum Genet 2014 Aug 13;133(8):997-1009. Epub 2014 Apr 13.

Institute of Human Genetics, University Medical Center Göttingen, Heinrich-Düker-Weg 12, 37073, Göttingen, Germany.

Heterozygous loss of function mutations in CHD7 (chromodomain helicase DNA-binding protein 7) lead to CHARGE syndrome, a complex developmental disorder affecting craniofacial structures, cranial nerves and several organ systems. Recently, it was demonstrated that CHD7 is essential for the formation of multipotent migratory neural crest cells, which migrate from the neural tube to many regions of the embryo, where they differentiate into various tissues including craniofacial and heart structures. So far, only few CHD7 target genes involved in neural crest cell development have been identified and the role of CHD7 in neural crest cell guidance and the regulation of mesenchymal-epithelial transition are unknown. Therefore, we undertook a genome-wide microarray expression analysis on wild-type and CHD7 deficient (Chd7 (Whi/+) and Chd7 (Whi/Whi)) mouse embryos at day 9.5, a time point of neural crest cell migration. We identified 98 differentially expressed genes between wild-type and Chd7 (Whi/Whi) embryos. Interestingly, many misregulated genes are involved in neural crest cell and axon guidance such as semaphorins and ephrin receptors. By performing knockdown experiments for Chd7 in Xenopus laevis embryos, we found abnormalities in the expression pattern of Sema3a, a protein involved in the pathogenesis of Kallmann syndrome, in vivo. In addition, we detected non-synonymous SEMA3A variations in 3 out of 45 CHD7-negative CHARGE patients. In summary, we discovered for the first time that Chd7 regulates genes involved in neural crest cell guidance, demonstrating a new aspect in the pathogenesis of CHARGE syndrome. Furthermore, we showed for Sema3a a conserved regulatory mechanism across different species, highlighting its significance during development. Although we postulated that the non-synonymous SEMA3A variants which we found in CHD7-negative CHARGE patients alone are not sufficient to produce the phenotype, we suggest an important modifier role for SEMA3A in the pathogenesis of this multiple malformation syndrome.
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http://dx.doi.org/10.1007/s00439-014-1444-2DOI Listing
August 2014

Mechanisms of natural gene therapy in dystrophic epidermolysis bullosa.

J Invest Dermatol 2014 Aug 27;134(8):2097-2104. Epub 2014 Feb 27.

Department of Dermatology, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands. Electronic address:

Revertant mosaicism has been reported in several inherited diseases, including the genetic skin fragility disorder epidermolysis bullosa (EB). Here, we describe the largest cohort of seven patients with revertant mosaicism and dystrophic EB (DEB), associated with mutations in the COL7A1 gene, and determine the underlying molecular mechanisms. We show that revertant mosaicism occurs both in autosomal dominantly and recessively inherited DEB. We found that null mutations resulting in complete loss of collagen VII and severe disease, as well as missense or splice-site mutations associated with some preserved collagen VII function and a milder phenotype, were corrected by revertant mosaicism. The mutation, subtype, and severity of the disease are thus not decisive for the presence of revertant mosaicism. Although collagen VII is synthesized and secreted by both keratinocytes and fibroblasts, evidence for reversion was only found in keratinocytes. The reversion mechanisms included back mutations/mitotic recombinations in 70% of the cases and second-site mutations affecting splicing in 30%. We conclude that revertant mosaicism is more common than previously assumed in patients with DEB, and our findings will have implications for future therapeutic strategies using the patient's naturally corrected cells as a source for cell-based therapies.
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http://dx.doi.org/10.1038/jid.2014.118DOI Listing
August 2014

Mutation of SALL2 causes recessive ocular coloboma in humans and mice.

Hum Mol Genet 2014 May 9;23(10):2511-26. Epub 2014 Jan 9.

Ulverscroft Vision Research Group.

Ocular coloboma is a congenital defect resulting from failure of normal closure of the optic fissure during embryonic eye development. This birth defect causes childhood blindness worldwide, yet the genetic etiology is poorly understood. Here, we identified a novel homozygous mutation in the SALL2 gene in members of a consanguineous family affected with non-syndromic ocular coloboma variably affecting the iris and retina. This mutation, c.85G>T, introduces a premature termination codon (p.Glu29*) predicted to truncate the SALL2 protein so that it lacks three clusters of zinc-finger motifs that are essential for DNA-binding activity. This discovery identifies SALL2 as the third member of the Drosophila homeotic Spalt-like family of developmental transcription factor genes implicated in human disease. SALL2 is expressed in the developing human retina at the time of, and subsequent to, optic fissure closure. Analysis of Sall2-deficient mouse embryos revealed delayed apposition of the optic fissure margins and the persistence of an anterior retinal coloboma phenotype after birth. Sall2-deficient embryos displayed correct posterior closure toward the optic nerve head, and upon contact of the fissure margins, dissolution of the basal lamina occurred and PAX2, known to be critical for this process, was expressed normally. Anterior closure was disrupted with the fissure margins failing to meet, or in some cases misaligning leading to a retinal lesion. These observations demonstrate, for the first time, a role for SALL2 in eye morphogenesis and that loss of function of the gene causes ocular coloboma in humans and mice.
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http://dx.doi.org/10.1093/hmg/ddt643DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3990155PMC
May 2014

The HNF4A R76W mutation causes atypical dominant Fanconi syndrome in addition to a β cell phenotype.

J Med Genet 2014 Mar 27;51(3):165-9. Epub 2013 Nov 27.

Institute of Biomedical and Clinical Science, University of Exeter Medical School, Exeter, Devon, UK.

Background: Mutation specific effects in monogenic disorders are rare. We describe atypical Fanconi syndrome caused by a specific heterozygous mutation in HNF4A. Heterozygous HNF4A mutations cause a beta cell phenotype of neonatal hyperinsulinism with macrosomia and young onset diabetes. Autosomal dominant idiopathic Fanconi syndrome (a renal proximal tubulopathy) is described but no genetic cause has been defined.

Methods And Results: We report six patients heterozygous for the p.R76W HNF4A mutation who have Fanconi syndrome and nephrocalcinosis in addition to neonatal hyperinsulinism and macrosomia. All six displayed a novel phenotype of proximal tubulopathy, characterised by generalised aminoaciduria, low molecular weight proteinuria, glycosuria, hyperphosphaturia and hypouricaemia, and additional features not seen in Fanconi syndrome: nephrocalcinosis, renal impairment, hypercalciuria with relative hypocalcaemia, and hypermagnesaemia. This was mutation specific, with the renal phenotype not being seen in patients with other HNF4A mutations. In silico modelling shows the R76 residue is directly involved in DNA binding and the R76W mutation reduces DNA binding affinity. The target(s) selectively affected by altered DNA binding of R76W that results in Fanconi syndrome is not known.

Conclusions: The HNF4A R76W mutation is an unusual example of a mutation specific phenotype, with autosomal dominant atypical Fanconi syndrome in addition to the established beta cell phenotype.
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http://dx.doi.org/10.1136/jmedgenet-2013-102066DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3932761PMC
March 2014

Biotin-responsive Basal Ganglia disease: a treatable differential diagnosis of leigh syndrome.

JIMD Rep 2014 29;13:53-7. Epub 2013 Oct 29.

Department of General Pediatrics, Neonatology and Pediatric Cardiology, University Children's Hospital, Heinrich-Heine University, Moorenstr. 5, D-40225, Düsseldorf, Germany,

Biotin-responsive basal ganglia disease (BBGD) is an autosomal recessive disorder, which is caused by mutations in the SLC19A3 gene. BBGD typically causes (sub)acute episodes with encephalopathy and subsequent neurological deterioration. If untreated, the clinical course may be fatal. Our report on a 6-year-old child with BBGD highlights that the disease is a crucial differential diagnosis of Leigh syndrome. Therefore, biotin and thiamine treatment is recommended for any patient with symmetrical basal ganglia lesions and neurological symptoms until BBGD is excluded. In addition, we exemplify that deformation-field-based morphometry of brain magnetic resonance images constitutes a novel quantitative tool, which might be very useful to monitor disease course and therapeutic effects in neurometabolic disorders.
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http://dx.doi.org/10.1007/8904_2013_271DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4110325PMC
July 2014

Extensive postzygotic mosaicism for a novel keratin 10 mutation in epidermolytic ichthyosis.

Acta Derm Venereol 2014 May;94(3):346-8

Department of Dermatology, University Medical Center, Freiburg, Germany.

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http://dx.doi.org/10.2340/00015555-1695DOI Listing
May 2014