Publications by authors named "Deborah J Morris-Rosendahl"

42 Publications

Cystic Fibrosis Lung Disease Modifiers and Their Relevance in the New Era of Precision Medicine.

Genes (Basel) 2021 Apr 13;12(4). Epub 2021 Apr 13.

Department of Paediatric Respiratory Medicine, Royal Brompton and Harefield Hospitals, London SW3 6NP, UK.

Our understanding of cystic fibrosis (CF) has grown exponentially since the discovery of the cystic fibrosis transmembrane conductance regulator () gene in 1989. With evolving genetic and genomic tools, we have come to better understand the role of genotypes in the pathophysiology of the disease. This, in turn, has paved the way for the development of modulator therapies targeted at mutations in the , which are arguably one of the greatest advances in the treatment of CF. These modulator therapies, however, do not target all the mutations in that are seen in patients with CF and, furthermore, a variation in response is seen in patients with the same genotype who are taking modulator therapies. There is growing evidence to support the role of non-CFTR modifiers, both genetic and environmental, in determining the variation seen in CF morbidity and mortality and also in the response to existing therapies. This review focusses on key findings from studies using candidate gene and genome-wide approaches to identify CF modifier genes of lung disease in cystic fibrosis and considers the interaction between modifiers and the response to modulator therapies. As the use of modulator therapies expands and we gain data around outcomes, it will be of great interest to investigate this interaction further. Going forward, it will also be crucial to better understand the relative influence of genomic versus environmental factors. With this understanding, we can truly begin to deliver personalised care by better profiling the likely disease phenotype for each patient and their response to treatment.
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http://dx.doi.org/10.3390/genes12040562DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8069009PMC
April 2021

Long QT and Silver Russell syndrome: First case report in a 9-year-old girl.

HeartRhythm Case Rep 2020 Sep 10;6(9):591-595. Epub 2020 Jun 10.

Clinical Genetics and Genomics, Royal Brompton and Harefield NHS Foundation Trust, London, United Kingdom.

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http://dx.doi.org/10.1016/j.hrcr.2020.06.003DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7498520PMC
September 2020

Neurodevelopmental disorders-the history and future of a diagnostic concept
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Dialogues Clin Neurosci 2020 03;22(1):65-72

Centre Hospitalier, Rouffach, France; CAMUHA, Université de Haute-Alsace, Mulhouse, France.

This article describes the history of the diagnostic class of neurodevelopmental disorders (NDDs) up to DSM-5. We further analyze how the development of genetics will transform the classification and diagnosis of NDDs. In DSM-5, NDDs include intellectual disability (ID), autism spectrum disorder (ASD), and attention-deficit/hyperactivity disorder (ADHD). Physicians in German-, French- and English-speaking countries (eg, Weikard, Georget, Esquirol, Down, Asperger, and Kanner) contributed to the phenomenological definitions of these disorders throughout the 18th and 20th centuries. These diagnostic categories show considerable comorbidity and phenotypic overlap. NDDs are one of the chapters of psychiatric nosology most likely to benefit from the approach advocated by the National Institute of Mental Health's Research Domain Criteria project. Genetic research supports the hypothesis that ID, ASD, ADHD, schizophrenia, and bipolar disorder lie on a neurodevelopmental continuum. The identification of recurrently observed copy number variants and disruptive gene variants in ASD (eg, CDH8, 16p11.2, SCN2A) led to the adoption of the genotype-first approach to characterize individuals at the etiological level.
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http://dx.doi.org/10.31887/DCNS.2020.22.1/macrocqDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7365295PMC
March 2020

Clinical utility of NGS diagnosis and disease stratification in a multiethnic primary ciliary dyskinesia cohort.

J Med Genet 2020 05 25;57(5):322-330. Epub 2019 Dec 25.

Host Defence Unit, Royal Brompton and Harefield NHS Trust, London, UK.

Background: Primary ciliary dyskinesia (PCD), a genetically heterogeneous condition enriched in some consanguineous populations, results from recessive mutations affecting cilia biogenesis and motility. Currently, diagnosis requires multiple expert tests.

Methods: The diagnostic utility of multigene panel next-generation sequencing (NGS) was evaluated in 161 unrelated families from multiple population ancestries.

Results: Most (82%) families had affected individuals with biallelic or hemizygous (75%) or single (7%) pathogenic causal alleles in known PCD genes. Loss-of-function alleles dominate (73% frameshift, stop-gain, splice site), most (58%) being homozygous, even in non-consanguineous families. Although 57% (88) of the total 155 diagnostic disease variants were novel, recurrent mutations and mutated genes were detected. These differed markedly between white European (52% of families carry or mutations), Arab (42% of families carry or mutations) and South Asian (single or mutations carried in 36% of families) patients, revealing a striking genetic stratification according to population of origin in PCD. Genetics facilitated successful diagnosis of 81% of families with normal or inconclusive ultrastructure and 67% missing prior ultrastructure results.

Conclusions: This study shows the added value of high-throughput targeted NGS in expediting PCD diagnosis. Therefore, there is potential significant patient benefit in wider and/or earlier implementation of genetic screening.
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http://dx.doi.org/10.1136/jmedgenet-2019-106501DOI Listing
May 2020

De Novo Mutations in FOXJ1 Result in a Motile Ciliopathy with Hydrocephalus and Randomization of Left/Right Body Asymmetry.

Am J Hum Genet 2019 11 17;105(5):1030-1039. Epub 2019 Oct 17.

Department of General Pediatrics, University Children's Hospital Muenster, 48149 Muenster, Germany. Electronic address:

Hydrocephalus is one of the most prevalent form of developmental central nervous system (CNS) malformations. Cerebrospinal fluid (CSF) flow depends on both heartbeat and body movement. Furthermore, it has been shown that CSF flow within and across brain ventricles depends on cilia motility of the ependymal cells lining the brain ventricles, which play a crucial role to maintain patency of the narrow sites of CSF passage during brain formation in mice. Using whole-exome and whole-genome sequencing, we identified an autosomal-dominant cause of a distinct motile ciliopathy related to defective ciliogenesis of the ependymal cilia in six individuals. Heterozygous de novo mutations in FOXJ1, which encodes a well-known member of the forkhead transcription factors important for ciliogenesis of motile cilia, cause a motile ciliopathy that is characterized by hydrocephalus internus, chronic destructive airway disease, and randomization of left/right body asymmetry. Mutant respiratory epithelial cells are unable to generate a fluid flow and exhibit a reduced number of cilia per cell, as documented by high-speed video microscopy (HVMA), transmission electron microscopy (TEM), and immunofluorescence analysis (IF). TEM and IF demonstrate mislocalized basal bodies. In line with this finding, the focal adhesion protein PTK2 displays aberrant localization in the cytoplasm of the mutant respiratory epithelial cells.
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http://dx.doi.org/10.1016/j.ajhg.2019.09.022DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6849114PMC
November 2019

Metabolomic, transcriptomic and genetic integrative analysis reveals important roles of adenosine diphosphate in haemostasis and platelet activation in non-small-cell lung cancer.

Mol Oncol 2019 11 30;13(11):2406-2421. Epub 2019 Sep 30.

National Heart and Lung Institute, Faculty of Medicine, Imperial College London, UK.

Lung cancer is the leading cause of cancer-related deaths in the world. The most prevalent subtype, accounting for 85% of cases, is non-small-cell lung cancer (NSCLC). Lung squamous cell carcinoma (LUSC) and lung adenocarcinoma (LUAD) are the most common subtypes. Despite recent advances in treatment, the low 5-year survival rate of NSCLC patients (approximately 13%) reflects the lack of early diagnostic biomarkers and incomplete understanding of the underlying disease mechanisms. We hypothesized that integration of metabolomic, transcriptomic and genetic profiles of tumours and matched normal tissues could help to identify important factors and potential therapeutic targets that contribute to tumorigenesis. We integrated omics profiles in tumours and matched adjacent normal tissues of patients with LUSC (N = 20) and LUAD (N = 17) using multiple system biology approaches. We confirmed the presence of previously described metabolic pathways in NSCLC, particularly those mediating the Warburg effect. In addition, through our combined omics analyses we found that metabolites and genes that contribute to haemostasis, angiogenesis, platelet activation and cell proliferation were predominant in both subtypes of NSCLC. The important roles of adenosine diphosphate in promoting cancer metastasis through platelet activation and angiogenesis suggest this metabolite could be a potential therapeutic target.
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http://dx.doi.org/10.1002/1878-0261.12568DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6822241PMC
November 2019

The role of genetics and genomics in clinical psychiatry.

Dialogues Clin Neurosci 2018 09;20(3):169-177

Clinical Genetics and Genomics, Royal Brompton and Harefield NHS Foundation Trust, London, UK, NHLI, Imperial College London, UK.

The enormous successes in the genetics and genomics of many diseases have provided the basis for the advancement of precision medicine. Thus, the detection of genetic variants associated with neuropsychiatric disorders, as well as treatment outcome, has raised growing expectations that these findings could soon be translated into the clinic to improve diagnosis, the prediction of disease risk and individual response to drug therapy. In this article, we will provide an introduction to the search for genes involved in psychiatric illness and summarize the present findings in major psychiatric disorders. We will review the genetic variants in genes encoding drug metabolizing enzymes and specific drug targets which were found to be associated with variable drug response and severe side effects. We will evaluate the clinical translatability of these findings, whether there is currently any role for genetic testing and in this context, make valuable sources of information available to the clinician seeking guidance and advice in this rapidly developing field of psychiatric genetics.
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http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6296395PMC
September 2018

CardioClassifier: disease- and gene-specific computational decision support for clinical genome interpretation.

Genet Med 2018 10 25;20(10):1246-1254. Epub 2018 Jan 25.

National Heart & Lung Institute, Imperial College London, London, UK.

Purpose: Internationally adopted variant interpretation guidelines from the American College of Medical Genetics and Genomics (ACMG) are generic and require disease-specific refinement. Here we developed CardioClassifier ( http://www.cardioclassifier.org ), a semiautomated decision-support tool for inherited cardiac conditions (ICCs).

Methods: CardioClassifier integrates data retrieved from multiple sources with user-input case-specific information, through an interactive interface, to support variant interpretation. Combining disease- and gene-specific knowledge with variant observations in large cohorts of cases and controls, we refined 14 computational ACMG criteria and created three ICC-specific rules.

Results: We benchmarked CardioClassifier on 57 expertly curated variants and show full retrieval of all computational data, concordantly activating 87.3% of rules. A generic annotation tool identified fewer than half as many clinically actionable variants (64/219 vs. 156/219, Fisher's P = 1.1  ×  10), with important false positives, illustrating the critical importance of disease and gene-specific annotations. CardioClassifier identified putatively disease-causing variants in 33.7% of 327 cardiomyopathy cases, comparable with leading ICC laboratories. Through addition of manually curated data, variants found in over 40% of cardiomyopathy cases are fully annotated, without requiring additional user-input data.

Conclusion: CardioClassifier is an ICC-specific decision-support tool that integrates expertly curated computational annotations with case-specific data to generate fast, reproducible, and interactive variant pathogenicity reports, according to best practice guidelines.
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http://dx.doi.org/10.1038/gim.2017.258DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6558251PMC
October 2018

Transplantation from a symptomatic carrier sister restores host defenses but does not prevent colitis in NEMO deficiency.

Clin Immunol 2016 Mar 23;164:52-6. Epub 2016 Jan 23.

Center of Chronic Immunodeficiency, University Medical Center Freiburg, Germany; Center for Pediatrics and Adolescent Medicine, University Medical Center Freiburg, Germany. Electronic address:

NF-κB essential modulator (NEMO) deficiency causes ectodermal dysplasia with immunodeficiency in males, while manifesting as incontinentia pigmenti in heterozygous females. We report a family with NEMO deficiency, in which a female carrier displayed skewed X-inactivation favoring the mutant NEMO allele associated with symptoms of Behçet's disease. Hematopoietic stem cell transplantation of an affected boy from this donor reconstituted an immune system with retained skewed X-inactivation. After transplantation no more severe infections occurred, indicating that an active wild-type NEMO allele in only 10% of immune cells restores host defense. Yet he developed inflammatory bowel disease (IBD). While gut infiltrating immune cells stained strongly for nuclear p65 indicating restored NEMO function, this was not the case in intestinal epithelial cells - in contrast to cells from conventional IBD patients. These results extend murine observations that epithelial NEMO-deficiency suffices to cause IBD. High anti-TNF doses controlled the intestinal inflammation and symptoms of Behçet's disease.
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http://dx.doi.org/10.1016/j.clim.2016.01.010DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6101191PMC
March 2016

Identification of two novel ALS2 mutations in infantile-onset ascending hereditary spastic paraplegia.

Amyotroph Lateral Scler Frontotemporal Degener 2016 11;17(3-4):260-5. Epub 2016 Jan 11.

b Institute of Human Genetics, University of Ulm , Ulm , Germany .

Biallelic mutations of ALS2 cause a clinical spectrum of overlapping autosomal recessive neurodegenerative disorders: infantile-onset ascending hereditary spastic paralysis (IAHSP), juvenile primary lateral sclerosis (JPLS), and juvenile amyotrophic lateral sclerosis (ALS2). We report on eleven individuals affected with IAHSP from two consanguineous Pakistani families. A combination of linkage analysis with homozygosity mapping and targeted sequencing identified two novel ALS2 mutations, a c.194T > C (p.Phe65Ser) missense substitution located in the first RCC-like domain of ALS2/alsin and a c.2998delA (p.Ile1000*) nonsense mutation. This study of extended families including a total of eleven affected individuals suggests that a given ALS2 mutation may lead to a phenotype with remarkable intrafamilial clinical homogeneity.
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http://dx.doi.org/10.3109/21678421.2015.1125501DOI Listing
January 2017

LIS1-associated classic lissencephaly: A retrospective, multicenter survey of the epileptogenic phenotype and response to antiepileptic drugs.

Brain Dev 2016 Apr 19;38(4):399-406. Epub 2015 Oct 19.

Center for and Institute of Human Genetics, University of Regensburg, Regensburg, Germany.

Background: Patients with LIS1-associated classic lissencephaly typically present with severe psychomotor retardation and drug-resistant epilepsy within the first year.

Aim: To analyze the epileptogenic phenotype and response to antiepileptic therapy in LIS1-associated classic lissencephaly.

Method: Retrospective evaluation of 22 patients (8 months-24 years) with genetically and radiologically confirmed LIS1-associated classic lissencephaly in 16 study centers.

Results: All patients in our cohort developed drug-resistant epilepsy. In 82% onset of seizures was noted within the first six months of life, most frequently with infantile spasms. Later in infancy the epileptogentic phenotype became more variable and included different forms of focal seizures as well generalized as tonic-clonic seizures, with generalized tonic-clonic seizures being the predominant type. Lamotrigine and valproate were rated most successful with good or partial response rates in 88-100% of the patients. Both were evaluated significantly better than levetiracetam (p<0.05) and sulthiame (p<0.01) in the neuropediatric assessment and better than levetiracetam, sulthiame (p<0.05) and topiramate (p<0.01) in the family survey. Phenobarbital and vigabatrin achieved good or partial response in 62-83% of the patients.

Conclusion: Our findings suggest that patients with LIS1-associated lissencephaly might benefit most from lamotrigine, valproate, vigabatrin or phenobarbital.
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http://dx.doi.org/10.1016/j.braindev.2015.10.001DOI Listing
April 2016

Mutation in the V2 vasopressin receptor gene, AVPR2, causes nephrogenic syndrome of inappropriate diuresis.

Kidney Int 2015 Nov 1;88(5):1070-8. Epub 2015 Jul 1.

Department of Physiology, Faculty of Medicine, Semmelweis University, Budapest, Hungary.

Nephrogenic syndrome of inappropriate antidiuresis (NSIAD) is a recently discovered rare disease caused by gain-of-function mutations of the V2 vasopressin receptor gene, AVPR2. To date, mutations of Phe229 and Arg137 have been identified as gain-of-function in the V2 vasopressin receptor (V2R). These receptor mutations lead to hyponatremia, which may lead to clinical symptoms in infants. Here we present a newly identified I130N substitution in exon 2 of the V2R gene in a family, causing NSIAD. This I130N mutation resulted in constitutive activity of the V2R with constitutive cyclic adenosine monophosphate (cAMP) generation in HEK293 cells. This basal activity could be blocked by the inverse agonist tolvaptan and arginine-vasopressin stimulation enhanced the cAMP production of I130N-V2R. The mutation causes a biased receptor conformation as the basal cAMP generation activity of I130N does not lead to interaction with β-arrestin. The constitutive activity of the mutant receptor caused constitutive dynamin-dependent and β-arrestin-independent internalization. The inhibition of basal internalization using dominant-negative dynamin resulted in an increased cell surface expression. In contrast to the constitutive internalization, agonist-induced endocytosis was β-arrestin dependent. Thus, tolvaptan could be used for treatment of hyponatremia in patients with NSIAD who carry the I130N-V2R mutation.
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http://dx.doi.org/10.1038/ki.2015.181DOI Listing
November 2015

What next-generation sequencing (NGS) technology has enabled us to learn about primary autosomal recessive microcephaly (MCPH).

Mol Cell Probes 2015 Oct 4;29(5):271-81. Epub 2015 Jun 4.

Department of Pediatric Neurology, Charité University Medicine, Berlin, Germany; Institute of Cell Biology and Neurobiology, Charité University Medicine, Berlin, Germany.

The impact that next-generation sequencing technology (NGS) is having on many aspects of molecular and cell biology, is becoming increasingly apparent. One of the most noticeable outcomes of the new technology in human genetics, has been the accelerated rate of identification of disease-causing genes. Especially for rare, heterogeneous disorders, such as autosomal recessive primary microcephaly (MCPH), the handful of genes previously known to harbour disease-causing mutations, has grown at an unprecedented rate within a few years. Knowledge of new genes mutated in MCPH over the last four years has contributed to our understanding of the disorder at both the clinical and cellular levels. The functions of proteins such as WDR62, CASC5, PHC1, CDK6, CENP-E, CENP-F, CEP63, ZNF335, PLK4 and TUBGPC, have been added to the complex network of critical cellular processes known to be involved in brain growth and size. In addition to the importance of mitotic spindle assembly and structure, centrosome and centriole function and DNA repair and damage response, new mechanisms involving kinetochore-associated proteins and chromatin remodelling complexes have been elucidated. Two of the major contributions to our clinical knowledge are the realisation that primary microcephaly caused by mutations in genes at the MCPH loci is seldom an isolated clinical feature and is often accompanied either by additional cortical malformations or primordial dwarfism. Gene-phenotype correlations are being revisited, with a new dimension of locus heterogeneity and phenotypic variability being revealed.
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http://dx.doi.org/10.1016/j.mcp.2015.05.015DOI Listing
October 2015

BRF1 mutations alter RNA polymerase III-dependent transcription and cause neurodevelopmental anomalies.

Genome Res 2015 Feb 5;25(2):155-66. Epub 2015 Jan 5.

Institute of Human Genetics, University of Ulm, 89081 Ulm, Germany; Institute of Human Genetics, University Medical Center Hamburg-Eppendorf, 20246 Hamburg, Germany.

RNA polymerase III (Pol III) synthesizes tRNAs and other small noncoding RNAs to regulate protein synthesis. Dysregulation of Pol III transcription has been linked to cancer, and germline mutations in genes encoding Pol III subunits or tRNA processing factors cause neurogenetic disorders in humans, such as hypomyelinating leukodystrophies and pontocerebellar hypoplasia. Here we describe an autosomal recessive disorder characterized by cerebellar hypoplasia and intellectual disability, as well as facial dysmorphic features, short stature, microcephaly, and dental anomalies. Whole-exome sequencing revealed biallelic missense alterations of BRF1 in three families. In support of the pathogenic potential of the discovered alleles, suppression or CRISPR-mediated deletion of brf1 in zebrafish embryos recapitulated key neurodevelopmental phenotypes; in vivo complementation showed all four candidate mutations to be pathogenic in an apparent isoform-specific context. BRF1 associates with BDP1 and TBP to form the transcription factor IIIB (TFIIIB), which recruits Pol III to target genes. We show that disease-causing mutations reduce Brf1 occupancy at tRNA target genes in Saccharomyces cerevisiae and impair cell growth. Moreover, BRF1 mutations reduce Pol III-related transcription activity in vitro. Taken together, our data show that BRF1 mutations that reduce protein activity cause neurodevelopmental anomalies, suggesting that BRF1-mediated Pol III transcription is required for normal cerebellar and cognitive development.
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http://dx.doi.org/10.1101/gr.176925.114DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4315290PMC
February 2015

STIL mutation causes autosomal recessive microcephalic lobar holoprosencephaly.

Hum Genet 2015 Jan 14;134(1):45-51. Epub 2014 Sep 14.

Institute of Human Genetics, University of Ulm, Ulm, Germany.

Holoprosencephaly is a clinically and genetically heterogeneous midline brain malformation associated with neurologic manifestations including developmental delay, intellectual disability and seizures. Although mutations in the sonic hedgehog gene SHH and more than 10 other genes are known to cause holoprosencephaly, many patients remain without a molecular diagnosis. Here we show that a homozygous truncating mutation of STIL not only causes severe autosomal recessive microcephaly, but also lobar holoprosencephaly in an extended consanguineous Pakistani family. STIL mutations have previously been linked to centrosomal defects in primary microcephaly at the MCPH7 locus. Our results thus expand the clinical phenotypes associated with biallellic STIL mutations to include holoprosencephaly.
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http://dx.doi.org/10.1007/s00439-014-1487-4DOI Listing
January 2015

Severe presentation of WDR62 mutation: is there a role for modifying genetic factors?

Am J Med Genet A 2014 Sep 19;164A(9):2161-71. Epub 2014 May 19.

Department of Clinical Genetics, Erasmus Medical Center, Rotterdam, Germany.

Mutations in WDR62 are associated with primary microcephaly; however, they have been reported with wide phenotypic variability. We report on six individuals with novel WDR62 mutations who illustrate this variability and describe three in greater detail. Of the three, one lacks neuromotor development and has severe pachygyria on MRI, another has only delayed speech and motor development and moderate polymicrogyria, and the third has an intermediate phenotype. We observed a rare copy number change of unknown significance, a 17q25qter duplication, in the first severely affected individual. The 17q25 duplication included an interesting candidate gene, tubulin cofactor D (TBCD), crucial in microtubule assembly and disassembly. Sequencing of the non-duplicated allele showed a TBCD missense mutation, predicted to cause a deleterious p.Phe1121Val substitution. Sequencing of a cohort of five patients with WDR62 mutations, including one with an identical mutation and different phenotype, plus 12 individuals with diagnosis of microlissencephaly and another individual with mild intellectual disability (ID) and a 17q25 duplication, did not reveal TBCD mutations. However, immunostaining with tubulin antibodies of cells from patients with both WDR62 and TBCD mutation showed abnormal tubulin network when compared to controls and cells with only the WDR62 mutation. Therefore, we propose that genetic factors contribute to modify the severity of the WDR62 phenotype and, although based on suggestive evidence, TBCD could function as one of such factors.
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http://dx.doi.org/10.1002/ajmg.a.36611DOI Listing
September 2014

Skeletal muscle MRI of the lower limbs in congenital muscular dystrophy patients with novel POMT1 and POMT2 mutations.

Neuromuscul Disord 2014 Apr 28;24(4):321-4. Epub 2014 Jan 28.

Division of Neuropaediatrics, University of Basel Children's Hospital, Switzerland; Department of Neurology, University of Basel Hospital, Switzerland. Electronic address:

Alpha-dystroglycanopathies form a genetically heterogeneous group of congenital muscular dystrophies with a large variety of clinical phenotypes. Within this group mutations in the protein O-mannosyltransferase genes (POMT1 and POMT2) are known to cause a spectrum of CMD disorders including the Walker-Warburg Syndrome with severe brain and ocular malformations, and the limb girdle muscular dystrophy with and without mental retardation. In this case report the clinical phenotype and brain and muscle MRI findings of two siblings of 10 and 7years (male/female) homozygous for a novel mutation in the POMT1 gene (c.2220G>C, p.Trp740Cys) and a 10year old boy with two novel mutations in the POMT2 gene ((c.215G>A, p.Arg72His) and (c.713G>T, p.Gly238Val) are presented. Mutation detection was performed by direct sequencing of the FKRP, FKTN, POMT1 and POMT2 genes. T1-weighted axial muscle MRI of the lower limbs revealed diffuse fatty degeneration of thigh and calf muscles with predominance of gluteus maximus, adductor magnus, posterior thigh, medial gastrocnemius, and peroneus muscles, but no edematous changes. As a similar pattern of muscle involvement had been described in FKRP related α-dystroglycanopathy LGMD2I, we conclude that α-dystroglycanopathies may present with distinctive muscle MRI changes.
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http://dx.doi.org/10.1016/j.nmd.2014.01.009DOI Listing
April 2014

Lethal course of meconium ileus in preterm twins revealing a novel cystic fibrosis mutation (p.Cys524Tyr).

BMC Pediatr 2014 Jan 17;14:13. Epub 2014 Jan 17.

Department of Pediatrics, Albert-Ludwigs-University of Freiburg, Mathildenstrasse 1, D 79106 Freiburg, Germany.

Background: In term newborns meconium ileus is frequently associated with cystic fibrosis. Reports on meconium ileus in preterm infants being diagnosed with cystic fibrosis early after birth are very scarce. Associations between genotype and phenotype in cystic fibrosis and its particular comorbidities have been reported.

Case Presentation: Two extremely preterm twin infants (26 weeks of gestation) born from a Malaysian mother and a Caucasian father were presented with typical signs of meconium ileus. Despite immediate surgery both displayed a unique and finally lethal course. Mutation analysis revealed a novel, probably pathogenic cystic fibrosis mutation, p.Cys524Tyr. The novel mutation might explain the severity of disease next to typical sequelae of prematurity.

Conclusion: Preterm neonates with meconium ileus have to be evaluated for cystic fibrosis beyond ethnical boundaries, but may take devastating clinical courses despite early treatment. The novel, potentially pathogenic CF mutation p.Cys524Tyr might be associated with severe meconium ileus in neonates. Disease-modifying loci are important targets for intestinal comorbidity of cystic fibrosis.
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http://dx.doi.org/10.1186/1471-2431-14-13DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3898379PMC
January 2014

Loss-of-function mutations in TBC1D20 cause cataracts and male infertility in blind sterile mice and Warburg micro syndrome in humans.

Am J Hum Genet 2013 Dec 14;93(6):1001-14. Epub 2013 Nov 14.

Department of Cell Biology, Neurobiology, and Anatomy, Medical College of Wisconsin, Milwaukee, WI 53226, USA.

blind sterile (bs) is a spontaneous autosomal-recessive mouse mutation discovered more than 30 years ago. Phenotypically, bs mice exhibit nuclear cataracts and male infertility; genetic analyses assigned the bs locus to mouse chromosome 2. In this study, we first positionally cloned the bs locus and identified a putative causative mutation in the Tbc1d20 gene. Functional analysis established the mouse TBC1D20 protein as a GTPase-activating protein (GAP) for RAB1 and RAB2, and bs as a TBC1D20 loss-of-function mutation. Evaluation of bs mouse embryonic fibroblasts (mEFs) identified enlarged Golgi morphology and aberrant lipid droplet (LD) formation. Based on the function of TBC1D20 as a RABGAP and the bs cataract and testicular phenotypes, we hypothesized that mutations in TBC1D20 may contribute to Warburg micro syndrome (WARBM); WARBM constitutes a spectrum of disorders characterized by eye, brain, and endocrine abnormalities caused by mutations in RAB3GAP1, RAB3GAP2, and RAB18. Sequence analysis of a cohort of 77 families affected by WARBM identified five distinct TBC1D20 loss-of-function mutations, thereby establishing these mutations as causative of WARBM. Evaluation of human fibroblasts deficient in TBC1D20 function identified aberrant LDs similar to those identified in the bs mEFs. Additionally, our results show that human fibroblasts deficient in RAB18 and RAB3GAP1 function also exhibit aberrant LD formation. These findings collectively indicate that a defect in LD formation/metabolism may be a common cellular abnormality associated with WARBM, although it remains unclear whether abnormalities in LD metabolism are contributing to WARBM disease pathology.
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http://dx.doi.org/10.1016/j.ajhg.2013.10.011DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3852926PMC
December 2013

Microdeletion 5q14.3 and anomalies of brain development.

Am J Med Genet A 2013 Sep 4;161A(9):2124-33. Epub 2013 Jul 4.

Institute of Human Genetics, Albert-Ludwigs University Medical Centre Freiburg, Freiburg, Germany.

5q14.3 deletions spanning and flanking MEF2C as well as intragenic MEF2C mutations have recently been described as a cause of severe intellectual disability, epilepsy, and muscular hypotonia, with variable brain and other anomalies. With an increasing number of patients described, the clinical presentation of the patients appears to be relatively uniform, however the structural brain phenotypes described are variable. We describe two unrelated patients with overlapping de novo interstitial deletions of 4.1 and 1.9 Mb, including MEF2C in 5q14.3, one of whom had a complex brain malformation which could be best described as microcephaly with simplified gyral pattern (MSG). Expression analysis in both patients confirmed haploinsufficiency for MEF2C, decreased MECP2 expression and increased C3ORF58 (DIA1) expression, which is a new finding. A detailed analysis of brain and white matter abnormalities reported in patients with 5q14.3 deletion syndrome to date revealed a greater number of reported abnormalities in patients with deletions not including MEF2C than those with deletions or mutations directly affecting MEF2C. Screening an additional 43 patients with malformations of cerebral cortical development (MCD) for mutations in MEF2C and/or deletions in 5q14.3q15, did not detect any additional mutations, allowing us to conclude that 5q14.3 deletion syndrome is a rare cause of microcephaly with simplified gyral pattern.
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http://dx.doi.org/10.1002/ajmg.a.36020DOI Listing
September 2013

Clinical and cellular features in patients with primary autosomal recessive microcephaly and a novel CDK5RAP2 mutation.

Orphanet J Rare Dis 2013 Apr 15;8:59. Epub 2013 Apr 15.

Institute of Cell Biology and Neurobiology, Charité University Medicine, Berlin, Germany.

Background: Primary autosomal recessive microcephaly (MCPH) is a rare neurodevelopmental disorder that results in severe microcephaly at birth with pronounced reduction in brain volume, particularly of the neocortex, simplified cortical gyration and intellectual disability. Homozygous mutations in the Cyclin-dependent kinase 5 regulatory subunit-associated protein 2 gene CDK5RAP2 are the cause of MCPH3. Despite considerable interest in MCPH as a model disorder for brain development, the underlying pathomechanism has not been definitively established and only four pedigrees with three CDK5RAP2 mutations have been reported. Specifically for MCPH3, no detailed radiological or histological descriptions exist.

Methods/results: We sought to characterize the clinical and radiological features and pathological cellular processes that contribute to the human MCPH3 phenotype. Haplotype analysis using microsatellite markers around the MCPH1-7 and PNKP loci in an Italian family with two sons with primary microcephaly, revealed possible linkage to the MCPH3 locus. Sequencing of the coding exons and exon/intron splice junctions of the CDK5RAP2 gene identified homozygosity for the novel nonsense mutation, c.4441C > T (p.Arg1481*), in both affected sons. cMRI showed microcephaly, simplified gyral pattern and hypogenesis of the corpus callosum. The cellular phenotype was assessed in EBV-transformed lymphocyte cell lines established from the two affected sons and compared with healthy male controls. CDK5RAP2 protein levels were below detection level in immortalized lymphocytes from the patients. Moreover, mitotic spindle defects and disrupted γ-tubulin localization to the centrosome were apparent.

Conclusion: These results suggest that spindle defects and a disruption of centrosome integrity play an important role in the development of microcephaly in MCPH3.
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http://dx.doi.org/10.1186/1750-1172-8-59DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3639195PMC
April 2013

Mutations in STAMBP, encoding a deubiquitinating enzyme, cause microcephaly-capillary malformation syndrome.

Nat Genet 2013 May 31;45(5):556-62. Epub 2013 Mar 31.

Children's Hospital of Eastern Ontario Research Institute, University of Ottawa, Ottawa, Ontario, Canada.

Microcephaly-capillary malformation (MIC-CAP) syndrome is characterized by severe microcephaly with progressive cortical atrophy, intractable epilepsy, profound developmental delay and multiple small capillary malformations on the skin. We used whole-exome sequencing of five patients with MIC-CAP syndrome and identified recessive mutations in STAMBP, a gene encoding the deubiquitinating (DUB) isopeptidase STAMBP (STAM-binding protein, also known as AMSH, associated molecule with the SH3 domain of STAM) that has a key role in cell surface receptor-mediated endocytosis and sorting. Patient cell lines showed reduced STAMBP expression associated with accumulation of ubiquitin-conjugated protein aggregates, elevated apoptosis and insensitive activation of the RAS-MAPK and PI3K-AKT-mTOR pathways. The latter cellular phenotype is notable considering the established connection between these pathways and their association with vascular and capillary malformations. Furthermore, our findings of a congenital human disorder caused by a defective DUB protein that functions in endocytosis implicates ubiquitin-conjugate aggregation and elevated apoptosis as factors potentially influencing the progressive neuronal loss underlying MIC-CAP syndrome.
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http://dx.doi.org/10.1038/ng.2602DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4000253PMC
May 2013

Mutation spectrum in RAB3GAP1, RAB3GAP2, and RAB18 and genotype-phenotype correlations in warburg micro syndrome and Martsolf syndrome.

Hum Mutat 2013 May;34(5):686-96

MRC Human Genetics Unit, Medical Research Council and Institute of Genetics and Molecular Medicine, University of Edinburgh, Scotland, UK.

Warburg Micro syndrome and Martsolf syndrome (MS) are heterogeneous autosomal-recessive developmental disorders characterized by brain, eye, and endocrine abnormalities. Causative biallelic germline mutations have been identified in RAB3GAP1, RAB3GAP2, or RAB18, each of which encode proteins involved in membrane trafficking. This report provides an up to date overview of all known disease variants identified in 29 previously published families and 52 new families. One-hundred and forty-four Micro and nine Martsolf families were investigated, identifying mutations in RAB3GAP1 in 41% of cases, mutations in RAB3GAP2 in 7% of cases, and mutations in RAB18 in 5% of cases. These are listed in Leiden Open source Variation Databases, which was created by us for all three genes. Genotype-phenotype correlations for these genes have now established that the clinical phenotypes in Micro syndrome and MS represent a phenotypic continuum related to the nature and severity of the mutations present in the disease genes, with more deleterious mutations causing Micro syndrome and milder mutations causing MS. RAB18 has not yet been linked to the RAB3 pathways, but mutations in all three genes cause an indistinguishable phenotype, making it likely that there is some overlap. There is considerable genetic heterogeneity for these disorders and further gene identification will help delineate these pathways.
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http://dx.doi.org/10.1002/humu.22296DOI Listing
May 2013

Novel mutations including deletions of the entire OFD1 gene in 30 families with type 1 orofaciodigital syndrome: a study of the extensive clinical variability.

Hum Mutat 2013 Jan 17;34(1):237-47. Epub 2012 Oct 17.

Institute of Human Genetics, University Clinic Freiburg, Freiburg, Germany.

OFD1, now recognized as a ciliopathy, is characterized by malformations of the face, oral cavity and digits, and is transmitted as an X-linked condition with lethality in males. Mutations in OFD1 also cause X-linked Joubert syndrome (JBTS10) and Simpson-Golabi-Behmel syndrome type 2 (SGBS2). We have studied 55 sporadic and six familial cases of suspected OFD1. Comprehensive mutation analysis in OFD1 revealed mutations in 37 female patients from 30 families; 22 mutations have not been previously described including two heterozygous deletions spanning OFD1 and neighbouring genes. Analysis of clinical findings in patients with mutations revealed that oral features are the most reliable diagnostic criteria. A first, detailed evaluation of brain MRIs from seven patients with cognitive defects illustrated extensive variability with the complete brain phenotype consisting of complete agenesis of the corpus callosum, large single or multiple interhemispheric cysts, striking cortical infolding of gyri, ventriculomegaly, mild molar tooth malformation and moderate to severe cerebellar vermis hypoplasia. Although the OFD1 gene apparently escapes X-inactivation, skewed inactivation was observed in seven of 14 patients. The direction of skewing did not correlate with disease severity, reinforcing the hypothesis that additional factors contribute to the extensive intrafamilial variability.
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http://dx.doi.org/10.1002/humu.22224DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5497464PMC
January 2013

Lissencephaly and band heterotopia: LIS1, TUBA1A, and DCX mutations in Hungary.

J Child Neurol 2012 Dec 8;27(12):1534-40. Epub 2012 Mar 8.

Department of Pediatrics, Clinical Genetic Center, Medical and Health Science Center, University of Debrecen, Debrecen, Hungary.

The spectrum of lissencephaly ranges from absent (agyria) or decreased (pachygyria) convolutions to less severe malformation known as subcortical band heterotopia. Mutations involving LIS1 and TUBA1A result in the classic form of lissencephaly, whereas mutations of the DCX gene cause lissencephaly in males and subcortical band heterotopia in females. This report describes the clinical manifestations and imaging and genetic findings in 2 boys with lissencephaly and a girl with subcortical band heterotopia. An ovel mutation (c.83_84delAT, p.Tyr28Phefs*31) was identified in LIS1 in 1 of the boys with lissencephaly and another novel mutation (c.200delG, p.Ile68Leufs*87) was found in DCX in the girl with subcortical band heterotopia. The mutations appeared in the first half of the genes and are predicted to result in truncated proteins. A mutation was found in the TUBA1A gene (c.1205G>A, p.Arg402His) in the other boy. This mutation affects the folding of tubulin heterodimers, changing the interactions with proteins that bind microtubules.
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http://dx.doi.org/10.1177/0883073811436326DOI Listing
December 2012

The core FOXG1 syndrome phenotype consists of postnatal microcephaly, severe mental retardation, absent language, dyskinesia, and corpus callosum hypogenesis.

J Med Genet 2011 Jun 25;48(6):396-406. Epub 2011 Mar 25.

Institut für Humangenetik, Universitätsklinikum Hamburg-Eppendorf, Campus Forschung, Martinistraße 52, 20246 Hamburg, Germany.

Background: Submicroscopic deletions in 14q12 spanning FOXG1 or intragenic mutations have been reported in patients with a developmental disorder described as a congenital variant of Rett syndrome. This study aimed to further characterise and delineate the phenotype of FOXG1 mutation positive patients.

Method: The study mapped the breakpoints of a 2;14 translocation by fluorescence in situ hybridisation and analysed three chromosome rearrangements in 14q12 by cytogenetic analysis and/or array comparative genomic hybridisation. The FOXG1 gene was sequenced in 210 patients, including 129 patients with unexplained developmental disorders and 81 MECP2 mutation negative individuals.

Results: One known mutation, seen in two patients, and nine novel mutations of FOXG1 including two deletions, two chromosome rearrangements disrupting or displacing putative cis-regulatory elements from FOXG1, and seven sequence changes, are reported. Analysis of 11 patients in this study, and a further 15 patients reported in the literature, demonstrates a complex constellation of features including mild postnatal growth deficiency, severe postnatal microcephaly, severe mental retardation with absent language development, deficient social reciprocity resembling autism, combined stereotypies and frank dyskinesias, epilepsy, poor sleep patterns, irritability in infancy, unexplained episodes of crying, recurrent aspiration, and gastro-oesophageal reflux. Brain imaging studies reveal simplified gyral pattern and reduced white matter volume in the frontal lobes, corpus callosum hypogenesis, and variable mild frontal pachgyria.

Conclusions: These findings have significantly expanded the number of FOXG1 mutations and identified two affecting possible cis-regulatory elements. While the phenotype of the patients overlaps both classic and congenital Rett syndrome, extensive clinical evaluation demonstrates a distinctive and clinically recognisable phenotype which the authors suggest designating as the FOXG1 syndrome.
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http://dx.doi.org/10.1136/jmg.2010.087528DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5522617PMC
June 2011

A homozygous RAB3GAP2 mutation causes Warburg Micro syndrome.

Hum Genet 2011 Jan 22;129(1):45-50. Epub 2010 Oct 22.

Institute of Human Genetics, University of Cologne, Kerpener Str. 34, 50931, Cologne, Germany.

Warburg Micro syndrome and Martsolf syndrome are clinically overlapping autosomal recessive conditions characterized by congenital cataracts, microphthalmia, postnatal microcephaly, and developmental delay. The neurodevelopmental and ophthalmological phenotype is more severe in Warburg Micro syndrome in which cerebral malformations and severe motor and mental retardation are common. While biallelic loss-of-function mutations in RAB3GAP1 are present in the majority of patients with Warburg Micro syndrome; a hypomorphic homozygous splicing mutation of RAB3GAP2 has been reported in a single family with Martsolf syndrome. Here, we report a novel homozygous RAB3GAP2 small in-frame deletion, c.499_507delTTCTACACT (p.Phe167_Thr169del) that causes Warburg Micro syndrome in a girl from a consanguineous Turkish family presenting with congenital cataracts, microphthalmia, absent visually evoked potentials, microcephaly, polymicrogyria, hypoplasia of the corpus callosum, and severe developmental delay. No RAB3GAP2 mutations were detected in ten additional unrelated patients with RAB3GAP1-negative Warburg Micro syndrome, consistent with further genetic heterogeneity. In conclusion, we provide evidence that RAB3GAP2 mutations are not specific to Martsolf syndrome. Rather, our findings suggest that loss-of-function mutations of RAB3GAP1 as well as functionally severe RAB3GAP2 mutations cause Warburg Micro syndrome while hypomorphic RAB3GAP2 mutations can result in the milder Martsolf phenotype. Thus, a phenotypic severity gradient may exist in the RAB3GAP-associated disease continuum (the "Warburg-Martsolf syndrome") which is presumably determined by the mutant gene and the nature of the mutation.
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http://dx.doi.org/10.1007/s00439-010-0896-2DOI Listing
January 2011

Fukutin mutations in non-Japanese patients with congenital muscular dystrophy: less severe mutations predominate in patients with a non-Walker-Warburg phenotype.

Neuromuscul Disord 2011 Jan 18;21(1):20-30. Epub 2010 Oct 18.

Gaziantep Children's Hospital, Department of Pediatric Neurology, Gaziantep, Turkey.

Six genes including POMT1, POMT2, POMGNT1, FKRP, Fukutin (FKTN) and LARGE encode proteins involved in the glycosylation of α-dystroglycan (α-DG). Abnormal glycosylation of α-DG is a common finding in Walker-Warburg syndrome (WWS), muscle-eye-brain disease (MEB), Fukuyama congenital muscular dystrophy (FCMD), congenital muscular dystrophy types 1C and 1D and some forms of autosomal recessive limb-girdle muscular dystrophy (LGMD2I, LGMD2K, LGMD2M), and is associated with mutations in the above genes. FCMD, caused by mutations in Fukutin (FKTN), is most frequent in Japan, but an increasing number of FKTN mutations are being reported outside of Japan. We describe four new patients with FKTN mutations and phenotypes ranging from: severe WWS in a Greek-Croatian patient, to congenital muscular dystrophy and cobblestone lissencephaly resembling MEB-FCMD in two Turkish patients, and limb-girdle muscular dystrophy and no mental retardation in a German patient. Four of the five different FKTN mutations have not been previously described.
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http://dx.doi.org/10.1016/j.nmd.2010.08.007DOI Listing
January 2011
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