Publications by authors named "Angelika Rieß"

34 Publications

Bi-allelic loss-of-function variants in BCAS3 cause a syndromic neurodevelopmental disorder.

Am J Hum Genet 2021 06 21;108(6):1069-1082. Epub 2021 May 21.

Manchester Centre for Genomic Medicine, St Mary's Hospital, Manchester University NHS Foundation Trust, Health Innovation Manchester, Manchester M13 9WL, UK.

BCAS3 microtubule-associated cell migration factor (BCAS3) is a large, highly conserved cytoskeletal protein previously proposed to be critical in angiogenesis and implicated in human embryogenesis and tumorigenesis. Here, we established BCAS3 loss-of-function variants as causative for a neurodevelopmental disorder. We report 15 individuals from eight unrelated families with germline bi-allelic loss-of-function variants in BCAS3. All probands share a global developmental delay accompanied by pyramidal tract involvement, microcephaly, short stature, strabismus, dysmorphic facial features, and seizures. The human phenotype is less severe compared with the Bcas3 knockout mouse model and cannot be explained by angiogenic defects alone. Consistent with being loss-of-function alleles, we observed absence of BCAS3 in probands' primary fibroblasts. By comparing the transcriptomic and proteomic data based on probands' fibroblasts with those of the knockout mouse model, we identified similar dysregulated pathways resulting from over-representation analysis, while the dysregulation of some proposed key interactors could not be confirmed. Together with the results from a tissue-specific Drosophila loss-of-function model, we demonstrate a vital role for BCAS3 in neural tissue development.
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http://dx.doi.org/10.1016/j.ajhg.2021.04.024DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8206390PMC
June 2021

Long-term disease course of two patients with multiple sulfatase deficiency differs from metachromatic leukodystrophy in a broad cohort.

JIMD Rep 2021 Mar 8;58(1):80-88. Epub 2020 Dec 8.

Department of Neuropediatrics University Children's Hospital Tübingen Germany.

Multiple sulfatase deficiency (MSD) is a lysosomal storage disease caused by a deficiency of formylglycine-generating enzyme due to defects. MSD may be misdiagnosed as metachromatic leukodystrophy (MLD), as neurological and neuroimaging findings are similar, and arylsulfatase A (ARSA) deficiency and enhanced urinary sulfatide excretion may also occur. While ARSA deficiency seems a cause for neurological symptoms and later neurodegenerative disease course, deficiency of other sulfatases results in clinical features such as dysmorphism, dysostosis, or ichthyosis. We report on a girl and a boy of the same origin presenting with severe ARSA deficiency and neurological and neuroimaging features compatible with MLD. However, exome sequencing revealed not yet described homozygosity of the missense variant c.529G > C, p.Ala177Pro in . We asked whether dynamics of disease course differs between MSD and MLD. Comparison to a cohort of 59 MLD patients revealed different disease course concerning onset and disease progression in both MSD patients. The MSD patients showed first gross motor symptoms earlier than most patients with juvenile MLD (<10th percentile of Gross-Motor-Function in MLD [GMFC-MLD] 1). However, subsequent motor decline was more protracted (75th and 90th percentile of GMFC-MLD 2 (loss of independent walking) and 75th percentile of GMFC-MLD 5 (loss of any locomotion)). Language decline started clearly after 50th percentile of juvenile MLD and progressed rapidly. Thus, dynamics of disease course may be a further clue for the characterization of MSD. These data may contribute to knowledge of natural course of ultra-rare MSD and be relevant for counseling and therapy.
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http://dx.doi.org/10.1002/jmd2.12189DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7932862PMC
March 2021

Growth, development, and phenotypic spectrum of individuals with deletions of 2q33.1 involving SATB2.

Clin Genet 2021 Apr 13;99(4):547-557. Epub 2021 Jan 13.

Department of Cardiology, Boston Children's Hospital and Department of Pediatrics, Harvard Medical School, Boston, Massachusetts, USA.

SATB2-Associated syndrome (SAS) is an autosomal dominant, multisystemic, neurodevelopmental disorder due to alterations in SATB2 at 2q33.1. A limited number of individuals with 2q33.1 contiguous deletions encompassing SATB2 (ΔSAS) have been described in the literature. We describe 17 additional individuals with ΔSAS, review the phenotype of 33 previously published individuals with 2q33.1 deletions (n = 50, mean age = 8.5 ± 7.8 years), and provide a comprehensive comparison to individuals with other molecular mechanisms that result in SAS (non-ΔSAS). Individuals in the ΔSAS group were often underweight for age (20/41 = 49%) with a progressive decline in weight (95% CI = -2.3 to -1.1, p < 0.0001) and height (95% CI = -2.3 to -1.0, p < 0.0001) Z-score means from birth to last available measurement. ΔSAS individuals were often noted to have a broad spectrum of facial dysmorphism. A composite image of ΔSAS individuals generated by automated image analysis was distinct as compared to matched controls and non-ΔSAS individuals. We also present additional genotype-phenotype correlations for individuals in the ΔSAS group such as an increased risk for aortic root/ascending aorta dilation and primary pulmonary hypertension for those individuals with contiguous gene deletions that include COL3A1/COL5A2 and BMPR2, respectively. Based on these findings, we provide additional care recommendations for individuals with ΔSAS variants.
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http://dx.doi.org/10.1111/cge.13912DOI Listing
April 2021

Pre- and postnatal findings in a patient with a recombinant chromosome rec(8)(qter→q21.11::p23.3→qter) due to a paternal pericentric inversion inv(8)(p23.3q21.11) and review of the literature.

Am J Med Genet A 2020 11 16;182(11):2680-2684. Epub 2020 Aug 16.

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

Recombinant chromosome 8 (Rec8) syndrome (San Luis Valley [SLV] syndrome; OMIM #179613) is a rare chromosome disorder associated with intellectual disability, congenital heart defects, variable skeletal and urogenital anomalies, and dysmorphic features. It is characterized by a partial terminal deletion of 8p and a partial terminal duplication of 8q, which is usually due to meiotic recombination of a pericentric inversion of chromosome 8 of a healthy carrier parent. There are only few reports of cases with breakpoints defined at the molecular level by molecular karyotyping. We report on a case of Rec8 syndrome with previously unreported breakpoints in a male fetus with intrauterine growth restriction, hypogenesis of the corpus callosum, bilateral cleft lip/palate, and congenital heart defect. Cytogenetic analysis revealed a recombinant chromosome 8 [46,XY,rec(8)(qter→q21.11::p23.3→qter)] secondary to a paternal pericentric inversion [46,XY,inv(8)(p23.3q21.11)]. Molecular karyotyping correspondingly showed a terminal copy number loss of 1.4 Mb (arr[hg19] 8p23.3(158048_1514749)×1) and a terminal copy number gain of chromosome band 8q21.11q24.3 of 69.8 Mb (arr[hg19] 8q21.11q24.3(76477367_146295771)×3). To our knowledge, this is the fourth reported case diagnosed prenatally. We describe the postnatal clinical course of the male newborn. Furthermore, we review and compare the phenotypic features and breakpoints of 74 reported Rec8/SLV cases.
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http://dx.doi.org/10.1002/ajmg.a.61804DOI Listing
November 2020

Clinical and molecular description of 19 patients with GATAD2B-Associated Neurodevelopmental Disorder (GAND).

Eur J Med Genet 2020 Oct 17;63(10):104004. Epub 2020 Jul 17.

Center for Medical Genetics, Ghent University Hospital, Ghent, Belgium.

De novo pathogenic variants in the GATAD2B gene have been associated with a syndromic neurodevelopmental disorder (GAND) characterized by severe intellectual disability (ID), impaired speech, childhood hypotonia, and dysmorphic features. Since its first description in 2013, nine patients have been reported in case reports and a series of 50 patients was recently published, which is consistent with the relative frequency of GATAD2B pathogenic variants in public databases. We report the detailed phenotype of 19 patients from various ethnic backgrounds with confirmed pathogenic GATAD2B variants including intragenic deletions. All individuals presented developmental delay with a median age of 2.5 years for independent walking and of 3 years for first spoken words. GATAD2B variant carriers showed very little subsequent speech progress, two patients over 30 years of age remaining non-verbal. ID was mostly moderate to severe, with one profound and one mild case, which shows a wider spectrum of disease severity than previously reported. We confirm macrocephaly as a major feature in GAND (53%). Most common dysmorphic features included broad forehead, deeply set eyes, hypertelorism, wide nasal base, and pointed chin. Conversely, prenatal abnormalities, non-cerebral malformations, epilepsy, and autistic behavior were uncommon. Other features included feeding difficulties, behavioral abnormalities, and unspecific abnormalities on brain MRI. Improving our knowledge of the clinical phenotype is essential for correct interpretation of the molecular results and accurate patient management.
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http://dx.doi.org/10.1016/j.ejmg.2020.104004DOI Listing
October 2020

The impact of an audience response system on a summative assessment, a controlled field study.

BMC Med Educ 2020 Jul 13;20(1):218. Epub 2020 Jul 13.

Institute for Medical Education, Department for Education and Media, University of Bern, Bern, Switzerland.

Background: Audience response systems allow to activate the audience and to receive a direct feedback of participants during lectures. Modern systems do not require any proprietary hardware anymore. Students can directly respond on their smartphone. Several studies reported about a high level of satisfaction of students when audience response systems are used, however their impact on learning success is still unclear.

Methods: In order to evaluate the impact of an audience response system on the learning success we implemented the audience response system eduVote into a seminar series and performed a controlled crossover study on its impact on assessments. One hundred fifty-four students in nine groups were taught the same content. In four groups, eduVote was integrated for the first topic while five groups were taught this topic without the audience response systems. For a second topic, the groups were switched: Those groups who were taught before using eduVote were now taught without the audience response system and vice versa. We then analysed the impact of the audience response system on the students' performance in a summative assessment and specifically focused on questions dealing with the topic, for which the audience response system was used during teaching. We further assessed the students' perception on the use of eduVote using questionnaires.

Results: In our controlled crossover study we could not confirm an impact of the audience response system eduVote on long-term persistence i.e. the students' performance in the summative assessment. Our evaluation revealed that students assessed the use of eduVote very positively, felt stronger engaged and better motivated to deal with the respective topics and would prefer their integration into additional courses as well. In particular we identified that students who feel uncomfortable with answering questions in front of others profit from the use of an audience response system during teaching.

Conclusions: Audience response systems motivate and activate students and increase their engagement during classes. However, their impact on long-term persistence and summative assessments may be limited. Audience response systems, however, specifically allow activating students which cannot be reached by the traditional way of asking questions without such an anonymous tool.
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http://dx.doi.org/10.1186/s12909-020-02130-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7359272PMC
July 2020

Pontocerebellar hypoplasia type 11: Does the genetic defect determine timing of cerebellar pathology?

Eur J Med Genet 2020 Jul 28;63(7):103938. Epub 2020 Apr 28.

Institute of Medical Genetics and Applied Genomics, University of Tübingen, 72076, Tübingen, Germany; Centre for Rare Diseases, University of Tuebingen, 72076, Tübingen, Germany. Electronic address:

Pontocerebellar hypoplasia (PCH) comprises a clinically and genetically heterogeneous group of disorders characterized by hypoplasia and degeneration of the cerebellum and ventral pons. To date at least 18 different clinical subtypes of PCH associated with pathogenic variants in 19 different genes have been described. Only recently, bi-allelic variants in TBC1D23 have been reported as the underlying molecular defect in seven index cases with a suspected non-degenerative form of PCH, PCH type 11 (PCH11). We used exome sequencing to investigate an individual with global developmental delay, ataxia, seizures, and progressive PCH. Brain volume was evaluated over a disease course of 14 years using volumetric magnetic resonance imaging (MRI). Volume alterations were compared to age-matched controls as well as data from children with PCH2. We identified a homozygous frameshift variant in exon 9 of 18 of TBC1D23 predicting a loss of protein function. Brain morphometry revealed a pattern of pontine, brain stem, and supratentorial volume loss similar to PCH2 patients although less pronounced. Intriguingly, cerebral MRI findings at the age of 1 and 15 years clearly showed progressive atrophy of the cerebellum, especially the hemispheres. In four of the cases reported in the literature cerebellar hemispheres could be evaluated on the MRIs displayed, they also showed atrophic foliae. While pontine hypoplasia and pronounced microcephaly are in line with previous reports on PCH11, our observations of clearly postnatal atrophy of the cerebellum argues for a different pathomechanism than in the other forms of PCH and supports the hypothesis that TBC1D23 deficiency predominantly interferes with postnatal rather than with prenatal cerebellar development.
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http://dx.doi.org/10.1016/j.ejmg.2020.103938DOI Listing
July 2020

Genetic basis of neurodevelopmental disorders in 103 Jordanian families.

Clin Genet 2020 04 1;97(4):621-627. Epub 2020 Mar 1.

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

We recruited 103 families from Jordan with neurodevelopmental disorders (NDD) and patterns of inheritance mostly suggestive of autosomal recessive inheritance. In each family, we investigated at least one affected individual using exome sequencing and an in-house diagnostic variant interpretation pipeline including a search for copy number variation. This approach led us to identify the likely molecular defect in established disease genes in 37 families. We could identify 25 pathogenic nonsense and 11 missense variants as well as 3 pathogenic copy number variants and 1 repeat expansion. Notably, 11 of the disease-causal variants occurred de novo. In addition, we prioritized a homozygous frameshift variant in PUS3 in two sisters with intellectual disability. To our knowledge, PUS3 has been postulated only recently as a candidate disease gene for intellectual disability in a single family with three affected siblings. Our findings provide additional evidence to establish loss of PUS3 function as a cause of intellectual disability.
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http://dx.doi.org/10.1111/cge.13720DOI Listing
April 2020

Loss-of-function mutations in UDP-Glucose 6-Dehydrogenase cause recessive developmental epileptic encephalopathy.

Nat Commun 2020 01 30;11(1):595. Epub 2020 Jan 30.

Department of Pediatrics, Department of Neurology, & the Board of Governors Regenerative Medicine Institute, Cedars-Sinai Medical Center, Los Angeles, CA, USA.

Developmental epileptic encephalopathies are devastating disorders characterized by intractable epileptic seizures and developmental delay. Here, we report an allelic series of germline recessive mutations in UGDH in 36 cases from 25 families presenting with epileptic encephalopathy with developmental delay and hypotonia. UGDH encodes an oxidoreductase that converts UDP-glucose to UDP-glucuronic acid, a key component of specific proteoglycans and glycolipids. Consistent with being loss-of-function alleles, we show using patients' primary fibroblasts and biochemical assays, that these mutations either impair UGDH stability, oligomerization, or enzymatic activity. In vitro, patient-derived cerebral organoids are smaller with a reduced number of proliferating neuronal progenitors while mutant ugdh zebrafish do not phenocopy the human disease. Our study defines UGDH as a key player for the production of extracellular matrix components that are essential for human brain development. Based on the incidence of variants observed, UGDH mutations are likely to be a frequent cause of recessive epileptic encephalopathy.
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http://dx.doi.org/10.1038/s41467-020-14360-7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6992768PMC
January 2020

Heterozygous Variants in KMT2E Cause a Spectrum of Neurodevelopmental Disorders and Epilepsy.

Am J Hum Genet 2019 06 9;104(6):1210-1222. Epub 2019 May 9.

Institute of Medical Genetics and Applied Genomics, University of Tuebingen, Tuebingen 72076, Germany.

We delineate a KMT2E-related neurodevelopmental disorder on the basis of 38 individuals in 36 families. This study includes 31 distinct heterozygous variants in KMT2E (28 ascertained from Matchmaker Exchange and three previously reported), and four individuals with chromosome 7q22.2-22.23 microdeletions encompassing KMT2E (one previously reported). Almost all variants occurred de novo, and most were truncating. Most affected individuals with protein-truncating variants presented with mild intellectual disability. One-quarter of individuals met criteria for autism. Additional common features include macrocephaly, hypotonia, functional gastrointestinal abnormalities, and a subtle facial gestalt. Epilepsy was present in about one-fifth of individuals with truncating variants and was responsive to treatment with anti-epileptic medications in almost all. More than 70% of the individuals were male, and expressivity was variable by sex; epilepsy was more common in females and autism more common in males. The four individuals with microdeletions encompassing KMT2E generally presented similarly to those with truncating variants, but the degree of developmental delay was greater. The group of four individuals with missense variants in KMT2E presented with the most severe developmental delays. Epilepsy was present in all individuals with missense variants, often manifesting as treatment-resistant infantile epileptic encephalopathy. Microcephaly was also common in this group. Haploinsufficiency versus gain-of-function or dominant-negative effects specific to these missense variants in KMT2E might explain this divergence in phenotype, but requires independent validation. Disruptive variants in KMT2E are an under-recognized cause of neurodevelopmental abnormalities.
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http://dx.doi.org/10.1016/j.ajhg.2019.03.021DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6556837PMC
June 2019

Structural brain anomalies in patients with FOXG1 syndrome and in Foxg1+/- mice.

Ann Clin Transl Neurol 2019 Apr 3;6(4):655-668. Epub 2019 Mar 3.

Institut für Medizinische Genetik und angewandte Genomik Universitätsklinikum Tübingen Tübingen Germany.

Objective: FOXG1 syndrome is a rare neurodevelopmental disorder associated with heterozygous variants or chromosomal microaberrations in 14q12. The study aimed at assessing the scope of structural cerebral anomalies revealed by neuroimaging to delineate the genotype and neuroimaging phenotype associations.

Methods: We compiled 34 patients with a heterozygous (likely) pathogenic variant. Qualitative assessment of cerebral anomalies was performed by standardized re-analysis of all 34 MRI data sets. Statistical analysis of genetic, clinical and neuroimaging data were performed. We quantified clinical and neuroimaging phenotypes using severity scores. Telencephalic phenotypes of adult +/- mice were examined using immunohistological stainings followed by quantitative evaluation of structural anomalies.

Results: Characteristic neuroimaging features included corpus callosum anomalies (82%), thickening of the fornix (74%), simplified gyral pattern (56%), enlargement of inner CSF spaces (44%), hypoplasia of basal ganglia (38%), and hypoplasia of frontal lobes (29%). We observed a marked, filiform thinning of the rostrum as recurrent highly typical pattern of corpus callosum anomaly in combination with distinct thickening of the fornix as a characteristic feature. Thickening of the fornices was not reported previously in FOXG1 syndrome. Simplified gyral pattern occurred significantly more frequently in patients with early truncating variants. Higher clinical severity scores were significantly associated with higher neuroimaging severity scores. Modeling of heterozygosity in mouse brain recapitulated the associated abnormal cerebral morphology phenotypes, including the striking enlargement of the fornix.

Interpretation: Combination of specific corpus callosum anomalies with simplified gyral pattern and hyperplasia of the fornices is highly characteristic for FOXG1 syndrome.
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http://dx.doi.org/10.1002/acn3.735DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6469254PMC
April 2019

The Discovery of a LEMD2-Associated Nuclear Envelopathy with Early Progeroid Appearance Suggests Advanced Applications for AI-Driven Facial Phenotyping.

Am J Hum Genet 2019 04 21;104(4):749-757. Epub 2019 Mar 21.

Faculty of Medicine, University of Cologne, Cologne, 50931, Germany; Institute of Human Genetics, University Hospital Cologne, Cologne, 50931, Germany. Electronic address:

Over a relatively short period of time, the clinical geneticist's "toolbox" has been expanded by machine-learning algorithms for image analysis, which can be applied to the task of syndrome identification on the basis of facial photographs, but these technologies harbor potential beyond the recognition of established phenotypes. Here, we comprehensively characterized two individuals with a hitherto unknown genetic disorder caused by the same de novo mutation in LEMD2 (c.1436C>T;p.Ser479Phe), the gene which encodes the nuclear envelope protein LEM domain-containing protein 2 (LEMD2). Despite different ages and ethnic backgrounds, both individuals share a progeria-like facial phenotype and a distinct combination of physical and neurologic anomalies, such as growth retardation; hypoplastic jaws crowded with multiple supernumerary, yet unerupted, teeth; and cerebellar intention tremor. Immunofluorescence analyses of patient fibroblasts revealed mutation-induced disturbance of nuclear architecture, recapitulating previously published data in LEMD2-deficient cell lines, and additional experiments suggested mislocalization of mutant LEMD2 protein within the nuclear lamina. Computational analysis of facial features with two different deep neural networks showed phenotypic proximity to other nuclear envelopathies. One of the algorithms, when trained to recognize syndromic similarity (rather than specific syndromes) in an unsupervised approach, clustered both individuals closely together, providing hypothesis-free hints for a common genetic etiology. We show that a recurrent de novo mutation in LEMD2 causes a nuclear envelopathy whose prognosis in adolescence is relatively good in comparison to that of classical Hutchinson-Gilford progeria syndrome, and we suggest that the application of artificial intelligence to the analysis of patient images can facilitate the discovery of new genetic disorders.
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http://dx.doi.org/10.1016/j.ajhg.2019.02.021DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6451726PMC
April 2019

Monoallelic BMP2 Variants Predicted to Result in Haploinsufficiency Cause Craniofacial, Skeletal, and Cardiac Features Overlapping Those of 20p12 Deletions.

Am J Hum Genet 2017 Dec 30;101(6):985-994. Epub 2017 Nov 30.

Institute of Medical Genetics, University of Zurich, 8952 Schlieren-Zurich, Switzerland.

Bone morphogenetic protein 2 (BMP2) in chromosomal region 20p12 belongs to a gene superfamily encoding TGF-β-signaling proteins involved in bone and cartilage biology. Monoallelic deletions of 20p12 are variably associated with cleft palate, short stature, and developmental delay. Here, we report a cranioskeletal phenotype due to monoallelic truncating and frameshift BMP2 variants and deletions in 12 individuals from eight unrelated families that share features of short stature, a recognizable craniofacial gestalt, skeletal anomalies, and congenital heart disease. De novo occurrence and autosomal-dominant inheritance of variants, including paternal mosaicism in two affected sisters who inherited a BMP2 splice-altering variant, were observed across all reported families. Additionally, we observed similarity to the human phenotype of short stature and skeletal anomalies in a heterozygous Bmp2-knockout mouse model, suggesting that haploinsufficiency of BMP2 could be the primary phenotypic determinant in individuals with predicted truncating variants and deletions encompassing BMP2. These findings demonstrate the important role of BMP2 in human craniofacial, skeletal, and cardiac development and confirm that individuals heterozygous for BMP2 truncating sequence variants or deletions display a consistent distinct phenotype characterized by short stature and skeletal and cardiac anomalies without neurological deficits.
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http://dx.doi.org/10.1016/j.ajhg.2017.10.006DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5812889PMC
December 2017

FOXG1 syndrome: genotype-phenotype association in 83 patients with FOXG1 variants.

Genet Med 2018 01 29;20(1):98-108. Epub 2017 Jun 29.

CeGaT, Tübingen, Germany.

PurposeThe study aimed at widening the clinical and genetic spectrum and assessing genotype-phenotype associations in FOXG1 syndrome due to FOXG1 variants.MethodsWe compiled 30 new and 53 reported patients with a heterozygous pathogenic or likely pathogenic variant in FOXG1. We grouped patients according to type and location of the variant. Statistical analysis of molecular and clinical data was performed using Fisher's exact test and a nonparametric multivariate test.ResultsAmong the 30 new patients, we identified 19 novel FOXG1 variants. Among the total group of 83 patients, there were 54 variants: 20 frameshift (37%), 17 missense (31%), 15 nonsense (28%), and 2 in-frame variants (4%). Frameshift and nonsense variants are distributed over all FOXG1 protein domains; missense variants cluster within the conserved forkhead domain. We found a higher phenotypic variability than previously described. Genotype-phenotype association revealed significant differences in psychomotor development and neurological features between FOXG1 genotype groups. More severe phenotypes were associated with truncating FOXG1 variants in the N-terminal domain and the forkhead domain (except conserved site 1) and milder phenotypes with missense variants in the forkhead conserved site 1.ConclusionsThese data may serve for improved interpretation of new FOXG1 sequence variants and well-founded genetic counseling.
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http://dx.doi.org/10.1038/gim.2017.75DOI 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

Epilepsy is not a mandatory feature of STXBP1 associated ataxia-tremor-retardation syndrome.

Eur J Paediatr Neurol 2016 Jul 28;20(4):661-5. Epub 2016 Apr 28.

Department of Medical Genetics and Applied Genomics, University of Tübingen, Germany; Rare Disease Center Tübingen, University of Tübingen, Germany.

Background: Mutations in the STXBP1 gene (MUNC18-1) were first described to cause Ohtahara syndrome (Early infantile epileptic encephalopathy, EIEE)(12-14) characterized by very early infantile epileptic encephalopathy with frequent tonic spasms and a suppression-burst pattern on electroencephalogram. In the following years a wider phenotype was recognized having milder forms of epilepsies. All patients showed also intellectual disability and movement disorders.

Methods: Here, we present three female patients with an ataxia-tremor-retardation syndrome caused by a de novo STXBP1 mutation. Two of the girls were diagnosed through next-generation-sequencing as mutations in STXBP1 were not suspected. The third patient was diagnosed by targeted genetic testing due to its clinical features strikingly similar to the first two girls.

Results: The characteristic feature of our three patients is the lack of epilepsy which is in contrast to the majority of the patients with STXBP1 mutation.

Conclusion: Hence, epilepsy is not a mandatory feature of patients with a STXBP1 mutation.
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http://dx.doi.org/10.1016/j.ejpn.2016.04.005DOI Listing
July 2016

Genotype and phenotype in patients with Noonan syndrome and a RIT1 mutation.

Genet Med 2016 12 21;18(12):1226-1234. Epub 2016 Apr 21.

Institute of Human Genetics, University Hospital Magdeburg, Magdeburg, Germany.

Purpose: Noonan syndrome (NS) is an autosomal-dominant disorder characterized by craniofacial dysmorphism, growth retardation, cardiac abnormalities, and learning difficulties. It belongs to the RASopathies, which are caused by germ-line mutations in genes encoding components of the RAS mitogen-activated protein kinase (MAPK) pathway. RIT1 was recently reported as a disease gene for NS, but the number of published cases is still limited.

Methods: We sequenced RIT1 in 310 mutation-negative individuals with a suspected RASopathy and prospectively in individuals who underwent genetic testing for NS. Using a standardized form, we recorded clinical features of all RIT1 mutation-positive patients. Clinical and genotype data from 36 individuals with RIT1 mutation reported previously were reviewed.

Results: Eleven different RIT1 missense mutations, three of which were novel, were identified in 33 subjects from 28 families; codons 57, 82, and 95 represent mutation hotspots. In relation to NS of other genetic etiologies, prenatal abnormalities, cardiovascular disease, and lymphatic abnormalities were common in individuals with RIT1 mutation, whereas short stature, intellectual problems, pectus anomalies, and ectodermal findings were less frequent.

Conclusion: RIT1 is one of the major genes for NS. The RIT1-associated phenotype differs gradually from other NS subtypes, with a high prevalence of cardiovascular manifestations, especially hypertrophic cardiomyopathy, and lymphatic problems.Genet Med 18 12, 1226-1234.
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http://dx.doi.org/10.1038/gim.2016.32DOI Listing
December 2016

Genetic and neurodevelopmental spectrum of SYNGAP1-associated intellectual disability and epilepsy.

J Med Genet 2016 08 17;53(8):511-22. Epub 2016 Mar 17.

Svt. Luka's Institute of Child Neurology and Epilepsy, Moscow, Russia.

Objective: We aimed to delineate the neurodevelopmental spectrum associated with SYNGAP1 mutations and to investigate genotype-phenotype correlations.

Methods: We sequenced the exome or screened the exons of SYNGAP1 in a total of 251 patients with neurodevelopmental disorders. Molecular and clinical data from patients with SYNGAP1 mutations from other centres were also collected, focusing on developmental aspects and the associated epilepsy phenotype. A review of SYNGAP1 mutations published in the literature was also performed.

Results: We describe 17 unrelated affected individuals carrying 13 different novel loss-of-function SYNGAP1 mutations. Developmental delay was the first manifestation of SYNGAP1-related encephalopathy; intellectual disability became progressively obvious and was associated with autistic behaviours in eight patients. Hypotonia and unstable gait were frequent associated neurological features. With the exception of one patient who experienced a single seizure, all patients had epilepsy, characterised by falls or head drops due to atonic or myoclonic seizures, (myoclonic) absences and/or eyelid myoclonia. Triggers of seizures were frequent (n=7). Seizures were pharmacoresistant in half of the patients. The severity of the epilepsy did not correlate with the presence of autistic features or with the severity of cognitive impairment. Mutations were distributed throughout the gene, but spared spliced 3' and 5' exons. Seizures in patients with mutations in exons 4-5 were more pharmacoresponsive than in patients with mutations in exons 8-15.

Conclusions: SYNGAP1 encephalopathy is characterised by early neurodevelopmental delay typically preceding the onset of a relatively recognisable epilepsy comprising generalised seizures (absences, myoclonic jerks) and frequent triggers.
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http://dx.doi.org/10.1136/jmedgenet-2015-103451DOI Listing
August 2016

First report on concordant monozygotic twins with Silver-Russell syndrome and ICR1 hypomethylation.

Eur J Med Genet 2016 Jan 10;59(1):1-4. Epub 2015 Dec 10.

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

Twin pairs with the imprinting disorder Silver-Russell syndrome (SRS) have rarely been reported. All six monozygotic (MZ) twin pairs described so far were clinically discordant. In two of the four SRS twin pairs with molecularly proven 11p15.5 epimutation, the healthy twin also showed the molecular alteration in blood cells, but not in the other tested tissues. The clinical discordance is a well-known but poorly understood observation because MZ twins derive from the same zygote. For the second 11p15.5-associated imprinting disorder, Beckwith-Wiedemann syndrome, a larger number of twins has been described, here the majority of pairs are MZ but clinically discordant as well. Interestingly, there is a considerable preponderance of females among the MZ twins with BWS, and a functional link between altered imprinting and X chromosome inactivation has been suggested. We now describe two further MZ SRS twins with H19/IGF2:IG-DMR hypomethylation, including the first clinically concordant pair. By summarizing the existing data, an excess of females in MZ twins with SRS is observed, thus confirming the hypothesis that X-chromosome inactivation might trigger the inaccurate methylation of imprinted loci at least in female twin conceptions. The occurrence of a MZ concordant SRS twin pair is exceptional. The detailed molecular characterization of both siblings of a twin pair enables a reliable diagnosis, furthermore it allows insights in the etiology of twinning in association with (aberrant) imprinting marking.
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http://dx.doi.org/10.1016/j.ejmg.2015.12.003DOI Listing
January 2016

ADAMTSL4-associated isolated ectopia lentis: Further patients, novel mutations and a detailed phenotype description.

Am J Med Genet A 2015 Oct 14;167A(10):2376-81. Epub 2015 May 14.

Klinische Genetik, Universitätskinderklinik, Paracelsus Medizinische Privatuniversität, Salzburg, Austria.

ADAMTSL4 mutations seem to be the most common cause of isolated ectoplia lentis (EL) and thus are important concerning the differential diagnosis of connective tissue syndromes with EL as main feature. In this study, we describe an additional cohort of patients with apparently isolated EL. All underwent a detailed clinical exam with cardiac evaluation combined with ADAMTSL4 mutation analysis. Mutations were identified in 12/15 patients with EL. Besides the European founder mutation p. (Gln256Profs*38) we identified five further mutations not yet described in the literature: p. (Leu249Tyrfs*21), p. (Ala388Glyfs*8), p. (Arg746His), p. (Gly592Ser), and p. (Arg865His). Clinical evaluation showed common additional ocular features such as high myopia, but no major systemic findings. In particular: no dilatation of the aortic root was reported on. This report increases the total number of patients with ADAMTSL4 mutations reported on today and reviews in detail the clinical findings in all patients reported on to date demonstrate, that these patients have a mainly ocular phenotype. There are no consistent systemic findings. The differentiation between syndromic and isolated EL is crucial for the further surveillance, treatment, and counseling of these patients, especially in young children.
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http://dx.doi.org/10.1002/ajmg.a.37157DOI Listing
October 2015

Mutations in SEC24D, encoding a component of the COPII machinery, cause a syndromic form of osteogenesis imperfecta.

Am J Hum Genet 2015 Mar 12;96(3):432-9. Epub 2015 Feb 12.

Institute of Human Genetics, University of Cologne, 50931 Cologne, Germany. Electronic address:

As a result of a whole-exome sequencing study, we report three mutant alleles in SEC24D, a gene encoding a component of the COPII complex involved in protein export from the ER: the truncating mutation c.613C>T (p.Gln205(∗)) and the missense mutations c.3044C>T (p.Ser1015Phe, located in a cargo-binding pocket) and c.2933A>C (p.Gln978Pro, located in the gelsolin-like domain). Three individuals from two families affected by a similar skeletal phenotype were each compound heterozygous for two of these mutant alleles, with c.3044C>T being embedded in a 14 Mb founder haplotype shared by all three. The affected individuals were a 7-year-old boy with a phenotype most closely resembling Cole-Carpenter syndrome and two fetuses initially suspected to have a severe type of osteogenesis imperfecta. All three displayed a severely disturbed ossification of the skull and multiple fractures with prenatal onset. The 7-year-old boy had short stature and craniofacial malformations including macrocephaly, midface hypoplasia, micrognathia, frontal bossing, and down-slanting palpebral fissures. Electron and immunofluorescence microscopy of skin fibroblasts of this individual revealed that ER export of procollagen was inefficient and that ER tubules were dilated, faithfully reproducing the cellular phenotype of individuals with cranio-lentico-sutural dysplasia (CLSD). CLSD is caused by SEC23A mutations and displays a largely overlapping craniofacial phenotype, but it is not characterized by generalized bone fragility and presented with cataracts in the original family described. The cellular and morphological phenotypes we report are in concordance with the phenotypes described for the Sec24d-deficient fish mutants vbi (medaka) and bulldog (zebrafish).
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http://dx.doi.org/10.1016/j.ajhg.2015.01.002DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4375534PMC
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

Genome-wide UPD screening in patients with intellectual disability.

Eur J Hum Genet 2014 Oct 7;22(10):1233-5. Epub 2014 May 7.

1] Institute of Medical Genetics and Applied Genomics, University of Tübingen, Tübingen, Germany [2] Rare Disease Center, University of Tübingen, Tübingen, Germany.

Uniparental disomy (UPD) describes the inheritance of a pair of chromosomes from only one parent. It may occur as isodisomy, heterodisomy or a combination of both and may involve only chromosome segments. UPD can affect each chromosome. The incidence is estimated to be around 1:3500 in live births. Some parts of chromosomes are subject to 'parent-of-origin imprinting' and the phenotypic effect in UPD syndromes is mainly due to functional imbalance of imprinted genes. Isodisomy can result in mutation homozygosity in autosomal-recessive inherited diseases. UPD causes several well-defined imprinting syndromes associated with intellectual disability (ID). Although knowledge on frequency and size of UPDs in patients with unexplained ID remains largely unknown as no efficient genome-wide screening technique was available for detection of both isodisomic and heterodisomic UPDs. SNP microarrays have been proven to be capable to detect UPDs through Mendelian errors. The correct subclassification of UPD requires child-parent trio experiments. To further elucidate the role of UPD in patients with unexplained ID, we analyzed a total of 322 child-parent trios. We were not able to detect UPDs (isodisomies and heterodisomies) within our cohort spanning whole chromosomes or chromosomal segments. We conclude that UPD is rare in patients with unexplained ID.
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http://dx.doi.org/10.1038/ejhg.2014.63DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4169544PMC
October 2014

X-linked intellectual disability type Nascimento is a clinically distinct, probably underdiagnosed entity.

Orphanet J Rare Dis 2013 Sep 21;8:146. Epub 2013 Sep 21.

Institut für Humangenetik, Universitätsklinikum Essen, Universität Duisburg-Essen, Hufelandstr, 55, 45122, Essen, Germany.

X-linked intellectual disability type Nascimento (MIM #300860), caused by mutations in UBE2A (MIM *312180), is characterized by craniofacial dysmorphism (synophrys, prominent supraorbital ridges, deep-set, almond-shaped eyes, depressed nasal bridge, prominent columella, hypoplastic alae nasi, and macrostomia), skin anomalies (hirsutism, myxedematous appearance, onychodystrophy), micropenis, moderate to severe intellectual disability (ID), motor delay, impaired/absent speech, and seizures. Hitherto only five familial point mutations and four different deletions including UBE2A have been reported in the literature.We present eight additional individuals from five families with UBE2A associated ID - three males from a consanguineous family, in whom we identified a small deletion of only 7.1 kb encompassing the first three exons of UBE2A, two related males with a UBE2A missense mutation in exon 4, a patient with a de novo nonsense mutation in exon 6, and two sporadic males with larger deletions including UBE2A. All affected male individuals share the typical clinical phenotype, all carrier females are unaffected and presented with a completely skewed X inactivation in blood. We conclude that 1.) X-linked intellectual disability type Nascimento is a clinically very distinct entity that might be underdiagnosed to date. 2.) So far, all females carrying a familial UBE2A aberration have a completely skewed X inactivation and are clinically unaffected. This should be taken in to account when counselling those families. 3.) The coverage of an array should be checked carefully prior to analysis since not all arrays have a sufficient resolution at specific loci, or alternative quantitative methods should be applied not to miss small deletions.
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http://dx.doi.org/10.1186/1750-1172-8-146DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4015352PMC
September 2013

PGAP2 mutations, affecting the GPI-anchor-synthesis pathway, cause hyperphosphatasia with mental retardation syndrome.

Am J Hum Genet 2013 Apr;92(4):584-9

Institute for Medical Genetics and Human Genetics, Charité Universitätsmedizin, 13353 Berlin, Germany.

Recently, mutations in genes involved in the biosynthesis of the glycosylphosphatidylinositol (GPI) anchor have been identified in a new subclass of congenital disorders of glycosylation (CDGs) with a distinct spectrum of clinical features. To date, mutations have been identified in six genes (PIGA, PIGL, PIGM, PIGN, PIGO, and PIGV) encoding proteins in the GPI-anchor-synthesis pathway in individuals with severe neurological features, including seizures, muscular hypotonia, and intellectual disability. We developed a diagnostic gene panel for targeting all known genes encoding proteins in the GPI-anchor-synthesis pathway to screen individuals matching these features, and we detected three missense mutations in PGAP2, c.46C>T, c.380T>C, and c.479C>T, in two unrelated individuals with hyperphosphatasia with mental retardation syndrome (HPMRS). The mutations cosegregated in the investigated families. PGAP2 is involved in fatty-acid GPI-anchor remodeling, which occurs in the Golgi apparatus and is required for stable association between GPI-anchored proteins and the cell-surface membrane rafts. Transfection of the altered protein constructs, p.Arg16Trp (NP_001243169.1), p.Leu127Ser, and p.Thr160Ile, into PGAP2-null cells showed only partial restoration of GPI-anchored marker proteins, CD55 and CD59, on the cell surface. In this work, we show that an impairment of GPI-anchor remodeling also causes HPMRS and conclude that targeted sequencing of the genes encoding proteins in the GPI-anchor-synthesis pathway is an effective diagnostic approach for this subclass of CDGs.
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http://dx.doi.org/10.1016/j.ajhg.2013.03.011DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3617374PMC
April 2013

Xq22.3-q23 deletion including ACSL4 in a patient with intellectual disability.

Am J Med Genet A 2013 Apr 12;161A(4):860-4. Epub 2013 Mar 12.

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

Mutations or deletions of ACSL4 (FACL4, OMIM 300157) are a rare cause of non-syndromic X-linked intellectual disability. We report on a 10-year-old male patient with moderate intellectual disability, sensorineural hearing loss, facial dysmorphism, pyloric stenosis, and intestinal obstruction in whom a de novo Xq22.3-q23 deletion was detected by SNP array analysis. The deleted 1.56 Mb interval harbored ACSL4 and eight neighboring genes (GUCY2F, NXT2, KCNE1L, TMEM164, MIR3978, AMMECR1, SNORD96B, and RGAG1). In contrast to previously reported patients with chromosome aberrations in the region of the AMME complex (Alport syndrome, intellectual disability, midface hypoplasia, and elliptocytosis, OMIM 300194), this deletion did not contain the Alport syndrome gene COL4A5, suggesting that loss of one or several of the other genes in this interval is responsible for the clinical problems. In summary, the patient reported here broadens our knowledge of the phenotypic consequences of deletions of chromosome region Xq22.3-q23 and provides further proof for ACSL4 as an X-linked intellectual disability gene.
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http://dx.doi.org/10.1002/ajmg.a.35778DOI Listing
April 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

Range of genetic mutations associated with severe non-syndromic sporadic intellectual disability: an exome sequencing study.

Lancet 2012 Nov 27;380(9854):1674-82. Epub 2012 Sep 27.

Institute of Medical Genetics, University of Zurich, Schwerzenbach-Zurich, Switzerland.

Background: The genetic cause of intellectual disability in most patients is unclear because of the absence of morphological clues, information about the position of such genes, and suitable screening methods. Our aim was to identify de-novo variants in individuals with sporadic non-syndromic intellectual disability.

Methods: In this study, we enrolled children with intellectual disability and their parents from ten centres in Germany and Switzerland. We compared exome sequences between patients and their parents to identify de-novo variants. 20 children and their parents from the KORA Augsburg Diabetes Family Study were investigated as controls.

Findings: We enrolled 51 participants from the German Mental Retardation Network. 45 (88%) participants in the case group and 14 (70%) in the control group had de-novo variants. We identified 87 de-novo variants in the case group, with an exomic mutation rate of 1·71 per individual per generation. In the control group we identified 24 de-novo variants, which is 1·2 events per individual per generation. More participants in the case group had loss-of-function variants than in the control group (20/51 vs 2/20; p=0·022), suggesting their contribution to disease development. 16 patients carried de-novo variants in known intellectual disability genes with three recurrently mutated genes (STXBP1, SYNGAP1, and SCN2A). We deemed at least six loss-of-function mutations in six novel genes to be disease causing. We also identified several missense alterations with potential pathogenicity.

Interpretation: After exclusion of copy-number variants, de-novo point mutations and small indels are associated with severe, sporadic non-syndromic intellectual disability, accounting for 45-55% of patients with high locus heterogeneity. Autosomal recessive inheritance seems to contribute little in the outbred population investigated. The large number of de-novo variants in known intellectual disability genes is only partially attributable to known non-specific phenotypes. Several patients did not meet the expected syndromic manifestation, suggesting a strong bias in present clinical syndrome descriptions.

Funding: German Ministry of Education and Research, European Commission 7th Framework Program, and Swiss National Science Foundation.
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http://dx.doi.org/10.1016/S0140-6736(12)61480-9DOI Listing
November 2012

Interstitial 3p25.3-p26.1 deletion in a patient with intellectual disability.

Am J Med Genet A 2012 Oct 10;158A(10):2587-90. Epub 2012 Sep 10.

Institute of Human Genetics, University of Tuebingen, Germany.

Interstitial deletions of the short arm of chromosome 3 are rare. We report on a 3-year-old girl with intellectual disability, muscular hypotonia, strabismus, and facial anomalies in whom an interstitial 1.24 Mb deletion in 3p25.3-p26.1 was detected by SNP array analysis. The deleted region harbors 11 RefSeq genes including CAV3 and SRGAP3/MEGAP, which had been associated with muscle disorders and intellectual disability, respectively. The deletion overlaps with a slightly larger deletion in a girl with a more complex phenotype including congenital heart defect and epilepsy, which indicates that haploinsufficiency of one or several of the genes in the deleted interval causes intellectual deficits, but not heart defects or epilepsy. Thus, the patient broadens our knowledge of the phenotypic consequences of deletions in 3p25.3-p26.1 and facilitates genotype-phenotype correlations for chromosome aberrations of this region.
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http://dx.doi.org/10.1002/ajmg.a.35562DOI Listing
October 2012

Miller (Genee-Wiedemann) syndrome represents a clinically and biochemically distinct subgroup of postaxial acrofacial dysostosis associated with partial deficiency of DHODH.

Hum Mol Genet 2012 Sep 12;21(18):3969-83. Epub 2012 Jun 12.

MRC Human Genetics Unit, Institute of Genetic and Molecular Medicine, University of Edinburgh, Edinburgh, UK.

Biallelic mutations in the gene encoding DHOdehase [dihydroorotate dehydrogenase (DHODH)], an enzyme required for de novo pyrimidine biosynthesis, have been identified as the cause of Miller (Genée-Weidemann or postaxial acrofacial dysostosis) syndrome (MIM 263750). We report compound heterozygous DHODH mutations in four additional families with typical Miller syndrome. Complementation in auxotrophic yeast demonstrated reduced pyrimidine synthesis and in vitro enzymatic analysis confirmed reduced DHOdehase activity in 11 disease-associated missense mutations, with 7 alleles showing discrepant activity between the assays. These discrepancies are partly explained by the domain structure of DHODH and suggest both assays are useful for interpretation of individual alleles. However, in all affected individuals, the genotype predicts that there should be significant residual DHOdehase activity. Urine samples obtained from two mutation-positive cases showed elevated levels of orotic acid (OA) but not dihydroorotate (DHO), an unexpected finding since these represent the product and the substrate of DHODH enzymatic activity, respectively. Screening of four unrelated cases with overlapping but atypical clinical features showed no mutations in either DHODH or the other de novo pyrimidine biosynthesis genes (CAD, UMPS), with these cases also showing normal levels of urinary OA and DHO. In situ analysis of mouse embryos showed Dhodh, Cad and Umps to be strongly expressed in the pharyngeal arch and limb bud, supporting a site- and stage-specific requirement for de novo pyrimidine synthesis. The developmental sensitivity to reduced pyrimidine synthesis capacity may reflect the requirement for an exceptional mitogenic response to growth factor signalling in the affected tissues.
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http://dx.doi.org/10.1093/hmg/dds218DOI Listing
September 2012
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