Publications by authors named "Rebecca Buchert"

25 Publications

  • Page 1 of 1

Bi-allelic HPDL Variants Cause a Neurodegenerative Disease Ranging from Neonatal Encephalopathy to Adolescent-Onset Spastic Paraplegia.

Am J Hum Genet 2020 08 23;107(2):364-373. Epub 2020 Jul 23.

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

We report bi-allelic pathogenic HPDL variants as a cause of a progressive, pediatric-onset spastic movement disorder with variable clinical presentation. The single-exon gene HPDL encodes a protein of unknown function with sequence similarity to 4-hydroxyphenylpyruvate dioxygenase. Exome sequencing studies in 13 families revealed bi-allelic HPDL variants in each of the 17 individuals affected with this clinically heterogeneous autosomal-recessive neurological disorder. HPDL levels were significantly reduced in fibroblast cell lines derived from more severely affected individuals, indicating the identified HPDL variants resulted in the loss of HPDL protein. Clinical presentation ranged from severe, neonatal-onset neurodevelopmental delay with neuroimaging findings resembling mitochondrial encephalopathy to milder manifestation of adolescent-onset, isolated hereditary spastic paraplegia. All affected individuals developed spasticity predominantly of the lower limbs over the course of the disease. We demonstrated through bioinformatic and cellular studies that HPDL has a mitochondrial localization signal and consequently localizes to mitochondria suggesting a putative role in mitochondrial metabolism. Taken together, these genetic, bioinformatic, and functional studies demonstrate HPDL is a mitochondrial protein, the loss of which causes a clinically variable form of pediatric-onset spastic movement disorder.
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http://dx.doi.org/10.1016/j.ajhg.2020.06.015DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7413886PMC
August 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

First-line exome sequencing in Palestinian and Israeli Arabs with neurological disorders is efficient and facilitates disease gene discovery.

Eur J Hum Genet 2020 08 25;28(8):1034-1043. Epub 2020 Mar 25.

Department of Neurology and Hertie-Institute for Clinical Brain Research, University of Tübingen, Tübingen, Germany.

A high rate of consanguinity leads to a high prevalence of autosomal recessive disorders in inbred populations. One example of inbred populations is the Arab communities in Israel and the Palestinian Authority. In the Palestinian Authority in particular, due to limited access to specialized medical care, most patients do not receive a genetic diagnosis and can therefore neither receive genetic counseling nor possibly specific treatment. We used whole-exome sequencing as a first-line diagnostic tool in 83 Palestinian and Israeli Arab families with suspected neurogenetic disorders and were able to establish a probable genetic diagnosis in 51% of the families (42 families). Pathogenic, likely pathogenic or highly suggestive candidate variants were found in the following genes extending and refining the mutational and phenotypic spectrum of these rare disorders: ACO2, ADAT3, ALS2, AMPD2, APTX, B4GALNT1, CAPN1, CLCN1, CNTNAP1, DNAJC6, GAMT, GPT2, KCNQ2, KIF11, LCA5, MCOLN1, MECP2, MFN2, MTMR2, NT5C2, NTRK1, PEX1, POLR3A, PRICKLE1, PRKN, PRX, SCAPER, SEPSECS, SGCG, SLC25A15, SPG11, SYNJ1, TMCO1, and TSEN54. Further, this cohort has proven to be ideal for prioritization of new disease genes. Two separately published candidate genes (WWOX and PAX7) were identified in this study. Analyzing the runs of homozygosity (ROHs) derived from the Exome sequencing data as a marker for the rate of inbreeding, revealed significantly longer ROHs in the included families compared with a German control cohort. The total length of ROHs correlated with the detection rate of recessive disease-causing variants. Identification of the disease-causing gene led to new therapeutic options in four families.
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http://dx.doi.org/10.1038/s41431-020-0609-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7382450PMC
August 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

Unraveling the genetic cause of hereditary ophthalmic disorders in Arab societies from Israel and the Palestinian Authority.

Eur J Hum Genet 2020 06 2;28(6):742-753. Epub 2020 Jan 2.

Institute for Ophthalmic Research, Molecular Genetics Laboratory, Tuebingen, Germany.

Visual impairment due to inherited ophthalmic disorders is amongst the most common disabilities observed in populations practicing consanguineous marriages. Here we investigated the molecular genetic basis of an unselected broad range of ophthalmic disorders in 20 consanguineous families from Arab villages of Israel and the Palestinian Authority. Most patients had little or very poor prior clinical workup and were recruited in a field study. Homozygosity mapping followed by candidate gene sequencing applying conventional Sanger sequencing or targeted next generation sequencing was performed in six families. In the remaining 14 families, one affected subject per family was chosen for whole exome sequencing. We discovered likely disease-causing variants, all homozygous, in 19 of 20 independent families (95%) including a previously reported novel disease gene for congenital nystagmus associated with foveal hypoplasia. Moreover, we found a family in which disease-causing variants for two collagenopathies - Stickler and Knobloch syndrome - segregate within a large sibship. Nine of the 19 distinct variants observed in this study were novel. Our study demonstrated a very high molecular diagnostic yield for a highly diverse spectrum of rare ophthalmic disorders in Arab patients from Israel and the Palestinian Authority, even with very limited prior clinical investigation. We conclude that 'genetic testing first' may be an economic way to direct clinical care and to support proper genetic counseling and risk assessment in these families.
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http://dx.doi.org/10.1038/s41431-019-0566-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7253446PMC
June 2020

Biallelic variants in the transcription factor PAX7 are a new genetic cause of myopathy.

Genet Med 2019 11 16;21(11):2521-2531. Epub 2019 May 16.

CHU Sainte-Justine Research Center, University of Montreal, Montreal, QC, Canada.

Purpose: Skeletal muscle growth and regeneration rely on muscle stem cells, called satellite cells. Specific transcription factors, particularly PAX7, are key regulators of the function of these cells. Knockout of this factor in mice leads to poor postnatal survival; however, the consequences of a lack of PAX7 in humans have not been established.

Methods: Here, we study five individuals with myopathy of variable severity from four unrelated consanguineous couples. Exome sequencing identified pathogenic variants in the PAX7 gene. Clinical examination, laboratory tests, and muscle biopsies were performed to characterize the disease.

Results: The disease was characterized by hypotonia, ptosis, muscular atrophy, scoliosis, and mildly dysmorphic facial features. The disease spectrum ranged from mild to severe and appears to be progressive. Muscle biopsies showed the presence of atrophic fibers and fibroadipose tissue replacement, with the absence of myofiber necrosis. A lack of PAX7 expression was associated with satellite cell pool exhaustion; however, the presence of residual myoblasts together with regenerating myofibers suggest that a population of PAX7-independent myogenic cells partially contributes to muscle regeneration.

Conclusion: These findings show that biallelic variants in the master transcription factor PAX7 cause a new type of myopathy that specifically affects satellite cell survival.
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http://dx.doi.org/10.1038/s41436-019-0532-zDOI Listing
November 2019

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.

Division of Genetics and Genomics, Boston Children's Hospital, Harvard Medical School, Boston, MA 02115, USA; Department of Neurology, Boston Children's Hospital, Harvard Medical School, Boston, MA 02115, USA. Electronic address:

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

Bain type of X-linked syndromic mental retardation in boys.

Clin Genet 2019 06 18;95(6):734-735. Epub 2019 Mar 18.

Department of General Pediatrics, Neonatology and Pediatric Cardiology, University Children's Hospital Duesseldorf, Medical Faculty, Heinrich Heine University, Duesseldorf, Germany.

A hemizygous variant in the HNRNPH2 gene causes MRXSB in a male individual.
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http://dx.doi.org/10.1111/cge.13524DOI Listing
June 2019

Two cases of variant late infantile ceroid lipofuscinosis in Jordan.

World J Clin Cases 2019 Jan;7(2):203-208

Department of Biotechnology and Genetic Engineering, Philadelphia University, Amman 11118, Jordan.

Background: Late infantile ceroid lipofuscinosis is a rare neurodegenerative disorder that appears between the ages of 2 and 4 years and is difficult to diagnose. In this report we present two sisters with this condition, and the clinical course consisted of delayed developmental skills initially and later regression of previously acquired skills. The cases were initially considered as childhood disintegrative disorder (CDD); however, when whole exome sequencing (WES) genetic testing was done, they proved to be variant late infantile ceroid lipofuscinosis. This is the first report from Jordan.

Case Summary: Clinical presentation included developmental delay and initially speech delay, followed by lose of sphincter control. Motor development was normal until 4 years of age, then they developed ataxia (fear of going downstairs) and weakness while walking. Atonic and myoclonic seizures become intractable, and this was followed by inability to stand or sit and loss of expressive language. In addition to complete blood count test, liver function test, kidney function test, serum electrolyte test, and blood sugar test, serum amino acid profile, B12 level test, thyroid function test, and a brain computed tomography scan were also normal. An electroencephalogram showed a generalized spike and wave pattern, and magnetic resonance imaging showed little to no abnormalities. After dealing with the cases as CDD, WES testing proved a final diagnosis of variant late infantile ceroid lipofuscinosis. Current treatment is anti-epileptic drugs and supportive care at home, and they are now in vegetative state.

Conclusion: This report highlights the importance of WES for the identification of genetic diseases, especially neurodegenerative disorders.
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http://dx.doi.org/10.12998/wjcc.v7.i2.203DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6354087PMC
January 2019

Homozygous TBC1 domain-containing kinase (TBCK) mutation causes a novel lysosomal storage disease - a new type of neuronal ceroid lipofuscinosis (CLN15)?

Acta Neuropathol Commun 2018 12 27;6(1):145. Epub 2018 Dec 27.

Department of Neuropathology, Philipps University and University Hospital of Marburg, Baldingerstrasse, 35043, Marburg, Germany.

Homozygous mutation of TBC1 domain-containing kinase (TBCK) is the cause of a very recently defined severe childhood disorder, which is characterized by severe hypotonia, global developmental delay, intellectual disability, epilepsy, characteristic facies and premature death. The link between TBCK loss of function and symptoms in patients with TBCK deficiency disorder (TBCK-DD) remains elusive. Here we demonstrate for the first time the histopathological characteristics of TBCK deficiency consisting of 1) a widespread and massive accumulation of lipofuscin storage material in neurons of the central nervous system without notable neuronal degeneration, 2) storage deposits in few astrocytes, 3) carbohydrate-rich deposits in brain, spleen and liver and 4) vacuolated lymphocytes. Biochemical examinations ruled out more than 20 known lysosomal storage diseases. These investigations strikingly uncover TBCK-DD as a novel type of lysosomal storage disease which is characterized by different storage products rather than one specific type of accumulated material. Due to the clear predominance of intraneuronal lipofuscin storage material and the characteristic clinical presentation we propose to classify this disease as a new subtype of neuronal ceroid lipofuscinosis (CLN15). Our results and previous reports suggest an autophagosomal-lysosomal dysfunction caused by enhanced mTORC1-mediated autophagosome formation and reduced Rab-mediated autophagosome-lysosome fusion, thus disclosing potential novel targets for therapeutic approaches in TBCK-DD.
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http://dx.doi.org/10.1186/s40478-018-0646-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6307319PMC
December 2018

Clinical presentation and natural history of infantile-onset ascending spastic paralysis from three families with an ALS2 founder variant.

Neurol Sci 2018 Nov 21;39(11):1917-1925. Epub 2018 Aug 21.

Molecular and Clinical Sciences Institute, St George's University of London, Cranmer Terrace, London, SW17 0RE, UK.

Biallelic mutations of the alsin Rho guanine nucleotide exchange factor (ALS2) gene cause a group of overlapping autosomal recessive neurodegenerative disorders including infantile-onset ascending hereditary spastic paralysis (IAHSP), juvenile primary lateral sclerosis (JPLS), and juvenile amyotrophic lateral sclerosis (JALS/ALS2), caused by retrograde degeneration of the upper motor neurons of the pyramidal tracts. Here, we describe 11 individuals with IAHSP, aged 2-48 years, with IAHSP from three unrelated consanguineous Iranian families carrying the homozygous c.1640+1G>A founder mutation in ALS2. Three affected siblings from one family exhibit generalized dystonia which has not been previously described in families with IAHSP and has only been reported in three unrelated consanguineous families with JALS/ALS2. We report the oldest individuals with IAHSP to date and provide evidence that these patients survive well into their late 40s with preserved cognition and normal eye movements. Our study delineates the phenotypic spectrum of IAHSP and ALS2-related disorders and provides valuable insights into the natural disease course.
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http://dx.doi.org/10.1007/s10072-018-3526-8DOI Listing
November 2018

De Novo Variants in the F-Box Protein FBXO11 in 20 Individuals with a Variable Neurodevelopmental Disorder.

Am J Hum Genet 2018 08 26;103(2):305-316. Epub 2018 Jul 26.

Institute of Human Genetics, Friedrich-Alexander-Universität Erlangen-Nürnberg, 91054 Erlangen, Germany. Electronic address:

Next-generation sequencing combined with international data sharing has enormously facilitated identification of new disease-associated genes and mutations. This is particularly true for genetically extremely heterogeneous entities such as neurodevelopmental disorders (NDDs). Through exome sequencing and world-wide collaborations, we identified and assembled 20 individuals with de novo variants in FBXO11. They present with mild to severe developmental delay associated with a range of features including short (4/20) or tall (2/20) stature, obesity (5/20), microcephaly (4/19) or macrocephaly (2/19), behavioral problems (17/20), seizures (5/20), cleft lip or palate or bifid uvula (3/20), and minor skeletal anomalies. FBXO11 encodes a member of the F-Box protein family, constituting a subunit of an E3-ubiquitin ligase complex. This complex is involved in ubiquitination and proteasomal degradation and thus in controlling critical biological processes by regulating protein turnover. The identified de novo aberrations comprise two large deletions, ten likely gene disrupting variants, and eight missense variants distributed throughout FBXO11. Structural modeling for missense variants located in the CASH or the Zinc-finger UBR domains suggests destabilization of the protein. This, in combination with the observed spectrum and localization of identified variants and the lack of apparent genotype-phenotype correlations, is compatible with loss of function or haploinsufficiency as an underlying mechanism. We implicate de novo missense and likely gene disrupting variants in FBXO11 in a neurodevelopmental disorder with variable intellectual disability and various other features.
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http://dx.doi.org/10.1016/j.ajhg.2018.07.003DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6080769PMC
August 2018

Isolated PREPL deficiency associated with congenital myasthenic syndrome-22.

Klin Padiatr 2018 09 18;230(5):281-283. Epub 2018 Jun 18.

Department of General Pediatrics, Heinrich-Heine-University, Duesseldorf, Germany.

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http://dx.doi.org/10.1055/a-0605-3659DOI Listing
September 2018

AMPA-receptor specific biogenesis complexes control synaptic transmission and intellectual ability.

Nat Commun 2017 07 4;8:15910. Epub 2017 Jul 4.

Institute of Physiology, Faculty of Medicine, University of Freiburg, Hermann-Herder-Str. 7, Freiburg 79104, Germany.

AMPA-type glutamate receptors (AMPARs), key elements in excitatory neurotransmission in the brain, are macromolecular complexes whose properties and cellular functions are determined by the co-assembled constituents of their proteome. Here we identify AMPAR complexes that transiently form in the endoplasmic reticulum (ER) and lack the core-subunits typical for AMPARs in the plasma membrane. Central components of these ER AMPARs are the proteome constituents FRRS1l (C9orf4) and CPT1c that specifically and cooperatively bind to the pore-forming GluA1-4 proteins of AMPARs. Bi-allelic mutations in the human FRRS1L gene are shown to cause severe intellectual disability with cognitive impairment, speech delay and epileptic activity. Virus-directed deletion or overexpression of FRRS1l strongly impact synaptic transmission in adult rat brain by decreasing or increasing the number of AMPARs in synapses and extra-synaptic sites. Our results provide insight into the early biogenesis of AMPARs and demonstrate its pronounced impact on synaptic transmission and brain function.
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http://dx.doi.org/10.1038/ncomms15910DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5500892PMC
July 2017

Hypomorphic Pathogenic Variants in TAF13 Are Associated with Autosomal-Recessive Intellectual Disability and Microcephaly.

Am J Hum Genet 2017 Mar;100(3):555-561

Institute of Human Genetics, Friedrich-Alexander-Universität Erlangen-Nürnberg, 91054 Erlangen, Germany; Institute of Human Genetics, University Medical Center Leipzig, 04103 Leipzig, Germany. Electronic address:

In two independent consanguineous families each with two children affected by mild intellectual disability and microcephaly, we identified two homozygous missense variants (c.119T>A [p.Met40Lys] and c.92T>A [p.Leu31His]) in TATA-box-binding-protein-associated factor 13 (TAF13). Molecular modeling suggested a pathogenic effect of both variants through disruption of the interaction between TAF13 and TAF11. These two proteins form a histone-like heterodimer that is essential for their recruitment into the general RNA polymerase II transcription factor IID (TFIID) complex. Co-immunoprecipitation in HeLa cells transfected with plasmids encoding TAF11 and TAF13 revealed that both variants indeed impaired formation of the TAF13-TAF11 heterodimer, thus confirming the protein modeling analysis. To further understand the functional role of TAF13, we performed RNA sequencing of neuroblastoma cell lines upon TAF13 knockdown. The transcriptional profile showed significant deregulation of gene expression patterns with an emphasis on genes related to neuronal and skeletal functions and those containing E-box motives in their promoters. Here, we expand the spectrum of TAF-associated phenotypes and highlight the importance of TAF13 in neuronal functions.
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http://dx.doi.org/10.1016/j.ajhg.2017.01.032DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5339287PMC
March 2017

Diagnostic Yield and Novel Candidate Genes by Exome Sequencing in 152 Consanguineous Families With Neurodevelopmental Disorders.

JAMA Psychiatry 2017 03;74(3):293-299

Institute of Human Genetics, Friedrich-Alexander-Universität Erlangen-Nürnberg, Erlangen, Germany2Institute of Human Genetics, University Medical Center Leipzig, Leipzig, Germany.

Importance: Autosomal recessive inherited neurodevelopmental disorders are highly heterogeneous, and many, possibly most, of the disease genes are still unknown.

Objectives: To promote the identification of disease genes through confirmation of previously described genes and presentation of novel candidates and provide an overview of the diagnostic yield of exome sequencing in consanguineous families.

Design, Setting, And Participants: Autozygosity mapping in families and exome sequencing of index patients were performed in 152 consanguineous families (the parents descended from a same ancestor) with at least 1 offspring with intellectual disability (ID). The study was conducted from July 1, 2008, to June 30, 2015, and data analysis was conducted from July 1, 2015, to August 31, 2016.

Results: Of the 152 consanguineous families enrolled, 1 child (in 45 families [29.6%]) or multiple children (107 families [70.4%]) had ID; additional features were present in 140 of the families (92.1%). The mean (SD) age of the children was 10.3 (9.0) years, and 171 of 297 (57.6%) were male. In 109 families (71.7%), potentially protein-disrupting and clinically relevant variants were identified. Of these, a clear clinical genetic diagnosis was made in 56 families (36.8%) owing to 57 (likely) pathogenic variants in 50 genes already established in neurodevelopmental disorders (46 autosomal recessive, 2 X-linked, and 2 de novo) or in 7 previously proposed recessive candidates. In 5 of these families, potentially treatable disorders were diagnosed (mutations in PAH, CBS, MTHFR, CYP27A1, and HIBCH), and in 1 family, 2 disease-causing homozygous variants in different genes were identified. In another 48 families (31.6%), 52 convincing recessive variants in candidate genes that were not previously reported in regard to neurodevelopmental disorders were identified. Of these, 14 were homozygous and truncating in GRM7, STX1A, CCAR2, EEF1D, GALNT2, SLC44A1, LRRIQ3, AMZ2, CLMN, SEC23IP, INIP, NARG2, FAM234B, and TRAP1. The diagnostic yield was higher in individuals with severe ID (35 of 77 [45.5%]), in multiplex families (42 of 107 [39.3%]), in patients with additional features (30 of 70 [42.9%]), and in those with remotely related parents (15 of 34 [44.1%]).

Conclusions And Relevance: Because of the high diagnostic yield of 36.8% and the possibility of identifying treatable diseases or the coexistence of several disease-causing variants, using exome sequencing as a first-line diagnostic approach in consanguineous families with neurodevelopmental disorders is recommended. Furthermore, the literature is enriched with 52 convincing candidate genes that are awaiting confirmation in independent families.
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http://dx.doi.org/10.1001/jamapsychiatry.2016.3798DOI Listing
March 2017

Epileptic Encephalopathy Caused by Mutations in the Guanine Nucleotide Exchange Factor DENND5A.

Am J Hum Genet 2016 Dec 17;99(6):1359-1367. Epub 2016 Nov 17.

Department of Neurology and Neurosurgery, Montreal Neurological Institute, McGill University, Montreal, QC H3A 2B4, Canada. Electronic address:

Epileptic encephalopathies are a catastrophic group of epilepsies characterized by refractory seizures and cognitive arrest, often resulting from abnormal brain development. Here, we have identified an epileptic encephalopathy additionally featuring cerebral calcifications and coarse facial features caused by recessive loss-of-function mutations in DENND5A. DENND5A contains a DENN domain, an evolutionarily ancient enzymatic module conferring guanine nucleotide exchange factor (GEF) activity to multiple proteins serving as GEFs for Rabs, which are key regulators of membrane trafficking. DENND5A is detected predominantly in neuronal tissues, and its highest levels occur during development. Knockdown of DENND5A leads to striking alterations in neuronal development. Mechanistically, these changes appear to result from upregulation of neurotrophin receptors, leading to enhanced downstream signaling. Thus, we have identified a link between a DENN domain protein and neuronal development, dysfunction of which is responsible for a form of epileptic encephalopathy.
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http://dx.doi.org/10.1016/j.ajhg.2016.10.006DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5142110PMC
December 2016

SPATA5 mutations cause a distinct autosomal recessive phenotype of intellectual disability, hypotonia and hearing loss.

Orphanet J Rare Dis 2016 Sep 29;11(1):130. Epub 2016 Sep 29.

Institute of Human Genetics, Friedrich-Alexander-University Erlangen-Nuremberg, 91054, Erlangen, Germany.

We examined an extended, consanguineous family with seven individuals with severe intellectual disability and microcephaly. Further symptoms were hearing loss, vision impairment, gastrointestinal disturbances, and slow and asymmetric waves in the EEG. Linkage analysis followed by exome sequencing revealed a homozygous variant in SPATA5 (c.1822_1824del; p.Asp608del), which segregates with the phenotype in the family. Molecular modelling suggested a deleterious effect of the identified alterations on the protein function. In an unrelated family, we identified compound heterozygous variants in SPATA5 (c.[2081G > A];[989_991delCAA]; p.[Gly694Glu];[.Thr330del]) in a further individual with global developmental delay, infantile spasms, profound dystonia, and sensorineural hearing loss. Molecular modelling suggested an impairment of protein function in the presence of both variants.SPATA5 is a member of the ATPase associated with diverse activities (AAA) protein family and was very recently reported in one publication to be mutated in individuals with intellectual disability, epilepsy and hearing loss. Our results describe new, probably pathogenic variants in SPATA5 that were identified in individuals with a comparable phenotype. We thus independently confirm that bi-allelic pathogenic variants in SPATA5 cause a syndromic form of intellectual disability, and we delineate its clinical presentation.
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http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5041579PMC
http://dx.doi.org/10.1186/s13023-016-0509-9DOI Listing
September 2016

Mutations in DCPS and EDC3 in autosomal recessive intellectual disability indicate a crucial role for mRNA decapping in neurodevelopment.

Hum Mol Genet 2015 Jun 20;24(11):3172-80. Epub 2015 Feb 20.

Institute of Human Genetics and

There are two known mRNA degradation pathways, 3' to 5' and 5' to 3'. We identified likely pathogenic variants in two genes involved in these two pathways in individuals with intellectual disability. In a large family with multiple branches, we identified biallelic variants in DCPS in three affected individuals; a splice site variant (c.636+1G>A) that results in an in-frame insertion of 45 nucleotides and a missense variant (c.947C>T; p.Thr316Met). DCPS decaps the cap structure generated by 3' to 5' exonucleolytic degradation of mRNA. In vitro decapping assays showed an ablation of decapping function for both variants in DCPS. In another family, we identified a homozygous mutation (c.161T>C; p.Phe54Ser) in EDC3 in two affected children. EDC3 stimulates DCP2, which decaps mRNAs at the beginning of the 5' to 3' degradation pathway. In vitro decapping assays showed that altered EDC3 is unable to enhance DCP2 decapping at low concentrations and even inhibits DCP2 decapping at high concentration. We show that individuals with biallelic mutations in these genes of seemingly central functions are viable and that these possibly lead to impairment of neurological functions linking mRNA decapping to normal cognition. Our results further affirm an emerging theme linking aberrant mRNA metabolism to neurological defects.
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http://dx.doi.org/10.1093/hmg/ddv069DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4424955PMC
June 2015

Inhibition of RAS activation due to a homozygous ezrin variant in patients with profound intellectual disability.

Hum Mutat 2015 Feb;36(2):270-8

Leibniz Institute for Age Research, Fritz Lipmann Institute, Jena, Germany.

Gain-of-function alterations in several components and modulators of the Ras-MAPK pathway lead to dysregulation of the pathway and cause a broad spectrum of autosomal dominant developmental disorders, collectively known as RASopathies. These findings demonstrate the importance of tight multilevel Ras regulation to safeguard signaling output and prevent aberrant activity. We have recently identified ezrin as a novel regulatory element required for Ras activation. Homozygosity mapping and exome sequencing have now revealed the first presumably disease-causing variant in the coding gene EZR in two siblings with a profound intellectual disability. Localization and membrane targeting of the altered ezrin protein appeared normal but molecular modeling suggested protein interaction surfaces to be disturbed. Functional analysis revealed that the altered ezrin protein is no longer able to bind Ras and facilitate its activation. Furthermore, expression of the altered ezrin protein in different cell lines resulted in abnormal cellular processes, including reduced proliferation and neuritogenesis, thus revealing a possible mechanism for its phenotype in humans. To our knowledge, this is the first report of an autosomal recessively inherited loss-of-function mutation causing reduced Ras activity and thus extends and complements the pathogenicity spectrum of known Ras-MAPK pathway disturbances.
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http://dx.doi.org/10.1002/humu.22737DOI Listing
February 2015

A peroxisomal disorder of severe intellectual disability, epilepsy, and cataracts due to fatty acyl-CoA reductase 1 deficiency.

Am J Hum Genet 2014 Nov 30;95(5):602-10. Epub 2014 Oct 30.

Institute of Human Genetics, Friedrich-Alexander-Universität Erlangen-Nürnberg, 91054 Erlangen, Germany. Electronic address:

Rhizomelic chondrodysplasia punctata (RCDP) is a group of disorders with overlapping clinical features including rhizomelia, chondrodysplasia punctata, coronal clefts, cervical dysplasia, congenital cataracts, profound postnatal growth retardation, severe intellectual disability, and seizures. Mutations in PEX7, GNPAT, and AGPS, all involved in the plasmalogen-biosynthesis pathway, have been described in individuals with RCDP. Here, we report the identification of mutations in another gene in plasmalogen biosynthesis, fatty acyl-CoA reductase 1 (FAR1), in two families affected by severe intellectual disability, early-onset epilepsy, microcephaly, congenital cataracts, growth retardation, and spasticity. Exome analyses revealed a homozygous in-frame indel mutation (c.495_507delinsT [p.Glu165_Pro169delinsAsp]) in two siblings from a consanguineous family and compound-heterozygous mutations (c.[787C>T];[1094A>G], p.[Arg263(∗)];[Asp365Gly]) in a third unrelated individual. FAR1 reduces fatty acids to their respective fatty alcohols for the plasmalogen-biosynthesis pathway. To assess the pathogenicity of the identified mutations, we transfected human embryonic kidney 293 cells with plasmids encoding FAR1 with either wild-type or mutated constructs and extracted the lipids from the cells. We screened the lipids with gas chromatography and mass spectrometry and found that all three mutations abolished the reductase activity of FAR1, given that no fatty alcohols could be detected. We also observed reduced plasmalogens in red blood cells in one individual to a range similar to that seen in individuals with RCDP, further supporting abolished FAR1 activity. We thus expand the spectrum of clinical features associated with defects in plasmalogen biosynthesis to include FAR1 deficiency as a cause of syndromic severe intellectual disability with cataracts, epilepsy, and growth retardation but without rhizomelia.
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http://dx.doi.org/10.1016/j.ajhg.2014.10.003DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4225589PMC
November 2014

Null mutation in PGAP1 impairing Gpi-anchor maturation in patients with intellectual disability and encephalopathy.

PLoS Genet 2014 May 1;10(5):e1004320. Epub 2014 May 1.

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

Many eukaryotic cell-surface proteins are anchored to the membrane via glycosylphosphatidylinositol (GPI). There are at least 26 genes involved in biosynthesis and remodeling of GPI anchors. Hypomorphic coding mutations in seven of these genes have been reported to cause decreased expression of GPI anchored proteins (GPI-APs) on the cell surface and to cause autosomal-recessive forms of intellectual disability (ARID). We performed homozygosity mapping and exome sequencing in a family with encephalopathy and non-specific ARID and identified a homozygous 3 bp deletion (p.Leu197del) in the GPI remodeling gene PGAP1. PGAP1 was not described in association with a human phenotype before. PGAP1 is a deacylase that removes an acyl-chain from the inositol of GPI anchors in the endoplasmic reticulum immediately after attachment of GPI to proteins. In silico prediction and molecular modeling strongly suggested a pathogenic effect of the identified deletion. The expression levels of GPI-APs on B lymphoblastoid cells derived from an affected person were normal. However, when those cells were incubated with phosphatidylinositol-specific phospholipase C (PI-PLC), GPI-APs were cleaved and released from B lymphoblastoid cells from healthy individuals whereas GPI-APs on the cells from the affected person were totally resistant. Transfection with wild type PGAP1 cDNA restored the PI-PLC sensitivity. These results indicate that GPI-APs were expressed with abnormal GPI structure due to a null mutation in the remodeling gene PGAP1. Our results add PGAP1 to the growing list of GPI abnormalities and indicate that not only the cell surface expression levels of GPI-APs but also the fine structure of GPI-anchors is important for the normal neurological development.
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http://dx.doi.org/10.1371/journal.pgen.1004320DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4006728PMC
May 2014

Mutations in the mitochondrial gene C12ORF65 lead to syndromic autosomal recessive intellectual disability and show genotype phenotype correlation.

Eur J Med Genet 2013 Nov 28;56(11):599-602. Epub 2013 Sep 28.

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

Homozygosity mapping and exome sequencing in two affected siblings of a consanguineous family with mild intellectual disability, spastic paraplegia, and strabismus revealed a homozygous premature stop mutation at codon 139 of C12ORF65. Two previous studies reported truncating mutations at positions 84 and 132 of the protein. However, symptoms of the referred patients were only partially overlapping. Considering our findings, we now conclude that truncating mutations in C12ORF65 lead to a variable phenotype with intellectual disability, spastic paraplegia, and ophthalmoplegia as common symptoms. Further, we confirm a genotype-phenotype correlation between increasing length of the truncated protein and decreasing severity of symptoms.
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http://dx.doi.org/10.1016/j.ejmg.2013.09.010DOI Listing
November 2013

Hypomorphic mutations in PGAP2, encoding a GPI-anchor-remodeling protein, cause autosomal-recessive intellectual disability.

Am J Hum Genet 2013 Apr;92(4):575-83

Wilhelm Johannsen Centre for Functional Genome Research, The Panum Institute, University of Copenhagen, Blegdamsvej 3B, DK-2200 Copenhagen N, Denmark.

PGAP2 encodes a protein involved in remodeling the glycosylphosphatidylinositol (GPI) anchor in the Golgi apparatus. After synthesis in the endoplasmic reticulum (ER), GPI anchors are transferred to the proteins and are remodeled while transported through the Golgi to the cell membrane. Germline mutations in six genes (PIGA, PIGL, PIGM, PIGV, PIGN, and PIGO) in the ER-located part of the GPI-anchor-biosynthesis pathway have been reported, and all are associated with phenotypes extending from malformation and lethality to severe intellectual disability, epilepsy, minor dysmorphisms, and elevated alkaline phosphatase (ALP). We performed autozygosity mapping and ultra-deep sequencing followed by stringent filtering and identified two homozygous PGAP2 alterations, p.Tyr99Cys and p.Arg177Pro, in seven offspring with nonspecific autosomal-recessive intellectual disability from two consanguineous families. Rescue experiments with the altered proteins in PGAP2-deficient Chinese hamster ovary cell lines showed less expression of cell-surface GPI-anchored proteins DAF and CD59 than of the wild-type protein, substantiating the pathogenicity of the identified alterations. Furthermore, we observed a full rescue when we used strong promoters before the mutant cDNAs, suggesting a hypomorphic effect of the mutations. We report on alterations in the Golgi-located part of the GPI-anchor-biosynthesis pathway and extend the phenotypic spectrum of the GPI-anchor deficiencies to isolated intellectual disability with elevated ALP. GPI-anchor deficiencies can be interpreted within the concept of a disease family, and we propose that the severity of the phenotype is dependent on the location of the altered protein in the biosynthesis chain.
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http://dx.doi.org/10.1016/j.ajhg.2013.03.008DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3617372PMC
April 2013

Adaptor protein complex 4 deficiency causes severe autosomal-recessive intellectual disability, progressive spastic paraplegia, shy character, and short stature.

Am J Hum Genet 2011 Jun 27;88(6):788-795. Epub 2011 May 27.

INSERM U781, Fondation IMAGINE, Département de Génétique and Département de Radiologie Pédiatrique, Université Paris Descartes, Hôpital Necker-Enfants Malades, 75015 Paris, France. Electronic address:

Intellectual disability inherited in an autosomal-recessive fashion represents an important fraction of severe cognitive-dysfunction disorders. Yet, the extreme heterogeneity of these conditions markedly hampers gene identification. Here, we report on eight affected individuals who were from three consanguineous families and presented with severe intellectual disability, absent speech, shy character, stereotypic laughter, muscular hypotonia that progressed to spastic paraplegia, microcephaly, foot deformity, decreased muscle mass of the lower limbs, inability to walk, and growth retardation. Using a combination of autozygosity mapping and either Sanger sequencing of candidate genes or next-generation exome sequencing, we identified one mutation in each of three genes encoding adaptor protein complex 4 (AP4) subunits: a nonsense mutation in AP4S1 (NM_007077.3: c.124C>T, p.Arg42(∗)), a frameshift mutation in AP4B1 (NM_006594.2: c.487_488insTAT, p.Glu163_Ser739delinsVal), and a splice mutation in AP4E1 (NM_007347.3: c.542+1_542+4delGTAA, r.421_542del, p.Glu181Glyfs(∗)20). Adaptor protein complexes (AP1-4) are ubiquitously expressed, evolutionarily conserved heterotetrameric complexes that mediate different types of vesicle formation and the selection of cargo molecules for inclusion into these vesicles. Interestingly, two mutations affecting AP4M1 and AP4E1 have recently been found to cause cerebral palsy associated with severe intellectual disability. Combined with previous observations, these results support the hypothesis that AP4-complex-mediated trafficking plays a crucial role in brain development and functioning and demonstrate the existence of a clinically recognizable syndrome due to deficiency of the AP4 complex.
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http://dx.doi.org/10.1016/j.ajhg.2011.04.019DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3113253PMC
June 2011