Publications by authors named "Elisa Rahikkala"

26 Publications

  • Page 1 of 1

Loss of DIAPH1 causes SCBMS, combined immunodeficiency, and mitochondrial dysfunction.

J Allergy Clin Immunol 2021 Mar 1. Epub 2021 Mar 1.

Institute for Molecular Medicine Finland (FIMM), HiLIFE, University of Helsinki, Helsinki, Finland; Centre for Molecular Medicine Norway (NCMM), University of Oslo, Oslo, Norway; Department of Medical Genetics, Oslo University Hospital, Oslo, Norway; Department of Clinical Genetics, Helsinki University Hospital, Helsinki, Finland. Electronic address:

Background: Homozygous loss of DIAPH1 results in seizures, cortical blindness, and microcephaly syndrome (SCBMS). We studied 5 Finnish and 2 Omani patients with loss of DIAPH1 presenting with SCBMS, mitochondrial dysfunction, and immunodeficiency.

Objective: We sought to further characterize phenotypes and disease mechanisms associated with loss of DIAPH1.

Methods: Exome sequencing, genotyping and haplotype analysis, B- and T-cell phenotyping, in vitro lymphocyte stimulation assays, analyses of mitochondrial function, immunofluorescence staining for cytoskeletal proteins and mitochondria, and CRISPR-Cas9 DIAPH1 knockout in heathy donor PBMCs were used.

Results: Genetic analyses found all Finnish patients homozygous for a rare DIAPH1 splice-variant (NM_005219:c.684+1G>A) enriched in the Finnish population, and Omani patients homozygous for a previously described pathogenic DIAPH1 frameshift-variant (NM_005219:c.2769delT;p.F923fs). In addition to microcephaly, epilepsy, and cortical blindness characteristic to SCBMS, the patients presented with infection susceptibility due to defective lymphocyte maturation and 3 patients developed B-cell lymphoma. Patients' immunophenotype was characterized by poor lymphocyte activation and proliferation, defective B-cell maturation, and lack of naive T cells. CRISPR-Cas9 knockout of DIAPH1 in PBMCs from healthy donors replicated the T-cell activation defect. Patient-derived peripheral blood T cells exhibited impaired adhesion and inefficient microtubule-organizing center repositioning to the immunologic synapse. The clinical symptoms and laboratory tests also suggested mitochondrial dysfunction. Experiments with immortalized, patient-derived fibroblasts indicated that DIAPH1 affects the amount of complex IV of the mitochondrial respiratory chain.

Conclusions: Our data demonstrate that individuals with SCBMS can have combined immune deficiency and implicate defective cytoskeletal organization and mitochondrial dysfunction in SCBMS pathogenesis.
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http://dx.doi.org/10.1016/j.jaci.2020.12.656DOI Listing
March 2021

X-linked myotubular myopathy mimics hereditary spastic paraplegia in two female manifesting carriers of pathogenic MTM1 variant.

Eur J Med Genet 2020 Nov 14;63(11):104040. Epub 2020 Aug 14.

PEDEGO Research Unit, Medical Research Center and Department of Clinical Genetics, University of Oulu and Oulu University Hospital, Oulu, Finland. Electronic address:

X-linked myotubular myopathy (XLMTM) is a rare congenital myopathy caused by pathogenic variants in the myotubularin 1 (MTM1) gene. XLMTM leads to severe weakness in male infants and majority of them die in the early postnatal period due to respiratory failure. Disease manifestations in female carriers vary from asymptomatic to severe, generalized congenital weakness. The symptomatic female carriers typically have limb-girdle weakness, asymmetric muscle weakness and skeletal size, urinary incontinence, facial weakness, ptosis and ophthalmoplegia. Here we describe a Finnish family with two females with lower limb spasticity and hyperreflexia resembling spastic paraplegia, gait difficulties and asymmetric muscle weakness in the limbs. A whole exome sequencing identified a heterozygous pathogenic missense variant MTM1 c.1262G > A, p.(Arg421Gln) segregating in the family. The variant has previously been detected in male and female patients with XLMTM. Muscle biopsy of one of the females showed variation in the myofiber diameter, atrophic myofibers, central nuclei and necklace fibers consistent with a diagnosis of XLMTM. This report suggests association between spastic paraplegia and pathogenic MTM1 variants expanding the phenotypic spectrum potentially associated with XLMTM, but the possible association needs to be confirmed by additional cases.
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http://dx.doi.org/10.1016/j.ejmg.2020.104040DOI Listing
November 2020

The CHD8 overgrowth syndrome: A detailed evaluation of an emerging overgrowth phenotype in 27 patients.

Am J Med Genet C Semin Med Genet 2019 12 13;181(4):557-564. Epub 2019 Nov 13.

South West Thames Regional Genetics Service, St George's University NHS Foundation Trust, London, UK.

CHD8 has been reported as an autism susceptibility/intellectual disability gene but emerging evidence suggests that it additionally causes an overgrowth phenotype. This study reports 27 unrelated patients with pathogenic or likely pathogenic CHD8 variants (25 null variants, two missense variants) and a male:female ratio of 21:6 (3.5:1, p < .01). All patients presented with intellectual disability, with 85% in the mild or moderate range, and 85% had a height and/or head circumference ≥2 standard deviations above the mean, meeting our clinical criteria for overgrowth. Behavioral problems were reported in the majority of patients (78%), with over half (56%) either formally diagnosed with an autistic spectrum disorder or described as having autistic traits. Additional clinical features included neonatal hypotonia (33%), and less frequently seizures, pes planus, scoliosis, fifth finger clinodactyly, umbilical hernia, and glabellar hemangioma (≤15% each). These results suggest that, in addition to its established link with autism and intellectual disability, CHD8 causes an overgrowth phenotype, and should be considered in the differential diagnosis of patients presenting with increased height and/or head circumference in association with intellectual disability.
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http://dx.doi.org/10.1002/ajmg.c.31749DOI Listing
December 2019

De Novo Variants in TAOK1 Cause Neurodevelopmental Disorders.

Am J Hum Genet 2019 07 20;105(1):213-220. Epub 2019 Jun 20.

Institute of Neurogenetics, University of Lübeck, 23538 Lübeck, Germany. Electronic address:

De novo variants represent a significant cause of neurodevelopmental delay and intellectual disability. A genetic basis can be identified in only half of individuals who have neurodevelopmental disorders (NDDs); this indicates that additional causes need to be elucidated. We compared the frequency of de novo variants in patient-parent trios with (n = 2,030) versus without (n = 2,755) NDDs. We identified de novo variants in TAOK1 (thousand and one [TAO] amino acid kinase 1), which encodes the serine/threonine-protein kinase TAO1, in three individuals with NDDs but not in persons who did not have NDDs. Through further screening and the use of GeneMatcher, five additional individuals with NDDs were found to have de novo variants. All eight variants were absent from gnomAD (Genome Aggregation Database). The variant carriers shared a non-specific phenotype of developmental delay, and six individuals had additional muscular hypotonia. We established a fibroblast line of one mutation carrier, and we demonstrated that reduced mRNA levels of TAOK1 could be increased upon cycloheximide treatment. These results indicate nonsense-mediated mRNA decay. Further, there was neither detectable phosphorylated TAO1 kinase nor phosphorylated tau in these cells, and mitochondrial morphology was altered. Knockdown of the ortholog gene Tao1 (Tao, CG14217) in Drosophila resulted in delayed early development. The majority of the Tao1-knockdown flies did not survive beyond the third instar larval stage. When compared to control flies, Tao1 knockdown flies revealed changed morphology of the ventral nerve cord and the neuromuscular junctions as well as a decreased number of endings (boutons). Furthermore, mitochondria in mutant flies showed altered distribution and decreased size in axons of motor neurons. Thus, we provide compelling evidence that de novo variants in TAOK1 cause NDDs.
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http://dx.doi.org/10.1016/j.ajhg.2019.05.005DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6612514PMC
July 2019

Novel variants and phenotypes widen the phenotypic spectrum of GABRG2-related disorders.

Seizure 2019 Jul 19;69:99-104. Epub 2019 Mar 19.

PEDEGO Research Unit, University of Oulu, Oulu, Finland; Medical Research Center, Oulu University Hospital, University of Oulu, Oulu, Finland; Biocenter Oulu, University of Oulu, Oulu, Finland; Department of Children and Adolescents, Division of Pediatric Neurology, Oulu University Hospital, Oulu, Finland.

Purpose: Next-generation sequencing (NGS) has made genetic testing of patients with epileptic encephalopathies easier - novel variants are discovered and new phenotypes described. Variants in the same gene - even the same variant - can cause different types of epilepsy and neurodevelopmental disorders. Our aim was to identify the genetic causes of epileptic encephalopathies in paediatric patients with complex phenotypes.

Methods: NGS was carried out for three patients with epileptic encephalopathies. Detailed clinical features, brain magnetic resonance imaging and electroencephalography were analysed. We searched the Human Gene Mutation Database for the published GABRG2 variants with clinical description of patients and composed a summary of the variants and their phenotypic features.

Results: We identified two novel de novo GABRG2 variants, p.P282T and p.S306F, with new phenotypes including neuroradiological evidence of neurodegeneration and epilepsy of infancy with migrating focal seizures (EIMFS). One patient carried previously reported p.P83S variant with autism spectrum disorder (ASD) phenotype that has not yet been described related to GABRG2 disorders and a more severe epilepsy phenotype than reported earlier. In all, the literature search yielded twenty-two articles describing 27 different variants that were divided into two categories: those with self-limiting epilepsies and febrile seizures and those with more severe drug-resistant epileptic encephalopathies.

Conclusion: This study further expands the genotypic and phenotypic spectrum of epilepsies associated with GABRG2 variants. More knowledge is still needed about the influence of the environment, genetic background and other epilepsy susceptibility genes on the phenotype of the specific GABRG2 variants.
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http://dx.doi.org/10.1016/j.seizure.2019.03.010DOI Listing
July 2019

Biallelic loss-of-function P4HTM gene variants cause hypotonia, hypoventilation, intellectual disability, dysautonomia, epilepsy, and eye abnormalities (HIDEA syndrome).

Genet Med 2019 10 3;21(10):2355-2363. Epub 2019 Apr 3.

PEDEGO Research Unit and Medical Research Centre Oulu, University of Oulu and Oulu University Hospital, Oulu, Finland.

Purpose: A new syndrome with hypotonia, intellectual disability, and eye abnormalities (HIDEA) was previously described in a large consanguineous family. Linkage analysis identified the recessive disease locus, and genome sequencing yielded three candidate genes with potentially pathogenic biallelic variants: transketolase (TKT), transmembrane prolyl 4-hydroxylase (P4HTM), and ubiquitin specific peptidase 4 (USP4). However, the causative gene remained elusive.

Methods: International collaboration and exome sequencing were used to identify new patients with HIDEA and biallelic, potentially pathogenic, P4HTM variants. Segregation analysis was performed using Sanger sequencing. P4H-TM wild-type and variant constructs without the transmembrane region were overexpressed in insect cells and analyzed using sodium dodecyl sulfate-polyacrylamide gel electrophoresis and western blot.

Results: Five different homozygous or compound heterozygous pathogenic P4HTM gene variants were identified in six new and six previously published patients presenting with HIDEA. Hypoventilation, obstructive and central sleep apnea, and dysautonomia were identified as novel features associated with the phenotype. Characterization of three of the P4H-TM variants demonstrated yielding insoluble protein products and, thus, loss-of-function.

Conclusions: Biallelic loss-of-function P4HTM variants were shown to cause HIDEA syndrome. Our findings enable diagnosis of the condition, and highlight the importance of assessing the need for noninvasive ventilatory support in patients.
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http://dx.doi.org/10.1038/s41436-019-0503-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6774999PMC
October 2019

Phenotypic spectrum associated with a CRADD founder variant underlying frontotemporal predominant pachygyria in the Finnish population.

Eur J Hum Genet 2019 08 26;27(8):1235-1243. Epub 2019 Mar 26.

Department of Medical Genetics, University of Helsinki, Helsinki, Finland.

Intellectual disability (ID), megalencephaly, frontal predominant pachygyria, and seizures, previously called "thin" lissencephaly, are reported to be caused by recessive variants in CRADD. Among five families of different ethnicities identified, one homozygous missense variant, c.509G>A p.(Arg170His), was of Finnish ancestry. Here we report on the phenotypic variability associated for this potential CRADD founder variant in 22 Finnish individuals. Exome sequencing was used to identify candidate genes in Finnish patients presenting with ID. Targeted Sanger sequencing and restriction enzyme analysis were applied to screen for the c.509G>A CRADD variant in cohorts from Finland. Detailed phenotyping and genealogical studies were performed. Twenty two patients were identified with the c.509G>A p.(Arg170His) homozygous variant in CRADD. The majority of the ancestors originated from Northeastern Finland indicating a founder effect. The hallmark of the disease is frontotemporal predominant pachygyria with mild cortical thickening. All patients show ID of variable severity. Aggressive behavior was found in nearly half of the patients, EEG abnormalities in five patients and megalencephaly in three patients. This study provides detailed data about the phenotypic spectrum of patients with lissencephaly due to a CRADD variant that affects function. High inter- and intrafamilial phenotypic heterogeneity was identified in patients with pachygyria caused by the homozygous CRADD founder variant. The phenotype variability suggests that additional genetic and/or environmental factors play a role in the clinical presentation. Since frontotemporal pachygyria is the hallmark of the disease, brain imaging studies are essential to support the molecular diagnosis for individuals with ID and a CRADD variant.
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http://dx.doi.org/10.1038/s41431-019-0383-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6777631PMC
August 2019

Contribution of rare and common variants to intellectual disability in a sub-isolate of Northern Finland.

Nat Commun 2019 01 24;10(1):410. Epub 2019 Jan 24.

Psychiatric & Neurodevelopmental Genetics Unit, Massachusetts General Hospital, Boston, MA, 02114, USA.

The contribution of de novo variants in severe intellectual disability (ID) has been extensively studied whereas the genetics of mild ID has been less characterized. To elucidate the genetics of milder ID we studied 442 ID patients enriched for mild ID (>50%) from a population isolate of Finland. Using exome sequencing, we show that rare damaging variants in known ID genes are observed significantly more often in severe (27%) than in mild ID (13%) patients. We further observe a significant enrichment of functional variants in genes not yet associated with ID (OR: 2.1). We show that a common variant polygenic risk significantly contributes to ID. The heritability explained by polygenic risk score is the highest for educational attainment (EDU) in mild ID (2.2%) but lower for more severe ID (0.6%). Finally, we identify a Finland enriched homozygote variant in the CRADD ID associated gene.
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http://dx.doi.org/10.1038/s41467-018-08262-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6345990PMC
January 2019

A mutation update on the LDS-associated genes TGFB2/3 and SMAD2/3.

Hum Mutat 2018 05 6;39(5):621-634. Epub 2018 Mar 6.

Center of Medical Genetics, University of Antwerp and Antwerp University Hospital, Antwerp, Belgium.

The Loeys-Dietz syndrome (LDS) is a connective tissue disorder affecting the cardiovascular, skeletal, and ocular system. Most typically, LDS patients present with aortic aneurysms and arterial tortuosity, hypertelorism, and bifid/broad uvula or cleft palate. Initially, mutations in transforming growth factor-β (TGF-β) receptors (TGFBR1 and TGFBR2) were described to cause LDS, hereby leading to impaired TGF-β signaling. More recently, TGF-β ligands, TGFB2 and TGFB3, as well as intracellular downstream effectors of the TGF-β pathway, SMAD2 and SMAD3, were shown to be involved in LDS. This emphasizes the role of disturbed TGF-β signaling in LDS pathogenesis. Since most literature so far has focused on TGFBR1/2, we provide a comprehensive review on the known and some novel TGFB2/3 and SMAD2/3 mutations. For TGFB2 and SMAD3, the clinical manifestations, both of the patients previously described in the literature and our newly reported patients, are summarized in detail. This clearly indicates that LDS concerns a disorder with a broad phenotypical spectrum that is still emerging as more patients will be identified. All mutations described here are present in the corresponding Leiden Open Variant Database.
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http://dx.doi.org/10.1002/humu.23407DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5947146PMC
May 2018

Correction: The genetic basis of classic nonketotic hyperglycinemia due to mutations in GLDC and AMT.

Genet Med 2018 09;20(9):1098

Section of Genetics, Department of Pediatrics, University of Colorado School of Medicine, Aurora, Colorado, USA.

The original supplementary information included with this article contained several minor errors. Corrected Supplementary Information accompanies this corrigendum.
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http://dx.doi.org/10.1038/gim.2017.232DOI Listing
September 2018

Adrenomyeloneuropathy due to mutation in the ABCD1 gene as underlying factor in spastic paraparesis.

Duodecim 2017;133(7):683-7

We present a Finnish family in which adrenomyeloneuropathy (AMN) caused by the mutation in the ABCD1 gene was revealed as the cause of spastic paraparesis. . Two patients had hypoadrenalism, which is in some cases some associated with the disease . AMN is a hereditary disease manifested both in men and women. but owing to the location of the gene in the X chromosome the symptoms are usually more severe in male patients. . Diagnoses was trucked down with gene-panel sequencing and confirmed through detection of an elevated level of very long-chain fatty acids in the serum of the patients. Specific molecular genetic diagnosis is beneficial, because it enables precise genetic counseling as well as recognition and treatment of associated symptoms, such as severe cortisol deficiency.
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January 2018

Ataxia-pancytopenia syndrome with mutations.

Neurol Genet 2017 Oct 24;3(5):e183. Epub 2017 Aug 24.

Sections of Neurology (S.G., C.N., A.P.), Pediatric Neurology (K.N.), Ophthalmology (S.A., U.K.), Pediatric Oncolocgy and Hematology (D.T., U.T., J.D.), Otorhinolaryngology (M.K.), and Hematology (L.N.), Department of Clinical Sciences, Skåne University Hospital, Lund University, Sweden; Department of Children and Adolescents (J.K.-E., J.U.), Department of Diagnostic Radiology (M.S.-P.), Department of Neurology (J.K.), and Department of Clinical Genetics, (E.R.), Oulu University Hospital; PEDEGO Research Unit (J.K.-E., E.R., J.U.), Medical Research Center Oulu (J.K.-E., M.S.-P., E.R., J.K., J.U.), Biocenter Oulu (J.K.-E., J.U.), and Research Unit of Clinical Neuroscience (J.K.), University of Oulu, Finland; Department of Hematology (J.C.), Linköping University Hospital and IKE Linköping University (J.C.), Sweden; and Division of Molecular Hematology (J.D.), Institution for Laboratory Medicine, Lund University, Sweden.

Objective: We describe the neurologic, neuroradiologic, and ophthalmologic phenotype of 1 Swedish and 1 Finnish family with autosomal dominant ataxia-pancytopenia (ATXPC) syndrome and mutations.

Methods: Members of these families with germline c.2956C>T, p.Arg986Cys, or c.2672T>C, p.Ile891Thr mutations underwent structured interviews and neurologic and ophthalmologic examinations. Neuroimaging was performed, and medical records were reviewed. Previous publications on -ATXPC were reviewed.

Results: Twelve individuals in both families were affected clinically. All mutation carriers examined had balance impairment, although severity was very variable. All but 1 had nystagmus, and all but 1 had pyramidal tract signs. Neurologic features were generally present from childhood on and progressed slowly. Two adult patients, who experienced increasing clumsiness, glare, and difficulties with gaze fixation, had paracentral retinal dysfunction verified by multifocal electroretinography. Brain MRI showed early, marked cerebellar atrophy in most carriers and variable cerebral periventricular white matter T2 hyperintensities. Two children were treated with hematopoietic stem cell transplantation for hematologic malignancies, and the neurologic symptoms of one of these worsened after treatment. Three affected individuals had attention deficit hyperactivity disorder or cognitive problems. Retinal dysfunction was not previously reported in individuals with ATXPC.

Conclusions: The neurologic phenotype of this syndrome is defined by balance or gait impairment, nystagmus, hyperreflexia in the lower limbs and, frequently, marked cerebellar atrophy. Paracentral retinal dysfunction may contribute to glare, reading problems, and clumsiness. Timely diagnosis of ATXPC is important to address the risk for severe hemorrhage, infection, and hematologic malignancies inherent in this syndrome; regular hematologic follow-up might be beneficial.
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http://dx.doi.org/10.1212/NXG.0000000000000183DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5570676PMC
October 2017

Intractable Epilepsy due to MTR Deficiency: Importance of Homocysteine Analysis.

Neuropediatrics 2017 12 30;48(6):467-472. Epub 2017 Jun 30.

PEDEGO Research Unit (Research Unit for Pediatrics, Pediatric Neurology, Pediatric Surgery, Child Psychiatry, Dermatology, Clinical Genetics, Obstetrics and Gynecology, Otorhinolaryngology and Ophthalmology), University of Oulu, Oulu, Finland.

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http://dx.doi.org/10.1055/s-0037-1603976DOI Listing
December 2017

Novel homozygous PCK1 mutation causing cytosolic phosphoenolpyruvate carboxykinase deficiency presenting as childhood hypoglycemia, an abnormal pattern of urine metabolites and liver dysfunction.

Mol Genet Metab 2017 04 6;120(4):337-341. Epub 2017 Feb 6.

Department of Pediatrics, Centre for Molecular Medicine and Therapeutics, BC Children's Hospital Research Institute, University of British Columbia, Vancouver, Canada; Department of Pediatrics, Emma Children's Hospital, Academic Medical Centre, Amsterdam, The Netherlands.

Clinical and laboratory data were collected from three Finnish patients including a sibling pair and another unrelated child with unexplained childhood hypoglycemia. Transient elevation of alanine transaminase, lactate and tricarboxylic acid cycle intermediates, especially fumarate, were noticed in urine organic acid analysis. Exome sequencing was performed for the patients and their parents. A novel homozygous PCK1 c.925G>A (p.G309R) mutation was detected in all affected individuals. COS-1 cells transfected with mutant PCK1 transcripts were used to study the pathogenic nature of the detected variant. The COS-1 transfected cells showed the mutant gene to be incapable of producing a normally functioning cytosolic phosphoenolpyruvate carboxykinase (PEPCK) enzyme. This report further delineates the clinical phenotype of isolated cytosolic PEPCK deficiency and offers a metabolic pattern helping to recognize these patients. Cytosolic PEPCK deficiency should be considered in the differential diagnosis of children presenting with hypoglycemia, hepatic dysfunction and elevated tricarboxylic acid intermediates in urinary organic acid analysis.
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http://dx.doi.org/10.1016/j.ymgme.2017.02.003DOI Listing
April 2017

Gain-of-function mutations cause a syndrome of cytopenia, immunodeficiency, MDS, and neurological symptoms.

Blood 2017 04 15;129(16):2266-2279. Epub 2017 Feb 15.

Centre for Hematology and Regenerative Medicine, Department of Medicine, Karolinska Institutet, Karolinska University Hospital Huddinge, Stockholm, Sweden.

Several monogenic causes of familial myelodysplastic syndrome (MDS) have recently been identified. We studied 2 families with cytopenia, predisposition to MDS with chromosome 7 aberrations, immunodeficiency, and progressive cerebellar dysfunction. Genetic studies uncovered heterozygous missense mutations in , a tumor suppressor gene located on chromosome arm 7q. Consistent with a gain-of-function effect, ectopic expression of the 2 identified SAMD9L mutants decreased cell proliferation relative to wild-type protein. Of the 10 individuals identified who were heterozygous for either mutation, 3 developed MDS upon loss of the mutated allele following intracellular infections associated with myeloid, B-, and natural killer (NK)-cell deficiency. Five other individuals, 3 with spontaneously resolved cytopenic episodes in infancy, harbored hematopoietic revertant mosaicism by uniparental disomy of 7q, with loss of the mutated allele or additional in truncating mutations. Examination of 1 individual indicated that somatic reversions were postnatally selected. Somatic mutations were tracked to CD34 hematopoietic progenitor cell populations, being further enriched in B and NK cells. Stimulation of these cell types with interferon (IFN)-α or IFN-γ induced SAMD9L expression. Clinically, revertant mosaicism was associated with milder disease, yet neurological manifestations persisted in 3 individuals. Two carriers also harbored a rare, in germ line missense loss-of-function variant, potentially counteracting the mutation. Our results demonstrate that gain-of-function mutations in the tumor suppressor cause cytopenia, immunodeficiency, variable neurological presentation, and predisposition to MDS with -7/del(7q), whereas hematopoietic revertant mosaicism commonly ameliorated clinical manifestations. The findings suggest a role for SAMD9L in regulating IFN-driven, demand-adapted hematopoiesis.
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http://dx.doi.org/10.1182/blood-2016-10-743302DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5399482PMC
April 2017

The genetic basis of classic nonketotic hyperglycinemia due to mutations in GLDC and AMT.

Genet Med 2017 01 30;19(1):104-111. Epub 2016 Jun 30.

Section of Genetics, Department of Pediatrics, University of Colorado School of Medicine, Aurora, Colorado, USA.

Purpose: The study's purpose was to delineate the genetic mutations that cause classic nonketotic hyperglycinemia (NKH).

Methods: Genetic results, parental phase, ethnic origin, and gender data were collected from subjects suspected to have classic NKH. Mutations were compared with those in the existing literature and to the population frequency from the Exome Aggregation Consortium (ExAC) database.

Results: In 578 families, genetic analyses identified 410 unique mutations, including 246 novel mutations. 80% of subjects had mutations in GLDC. Missense mutations were noted in 52% of all GLDC alleles, most private. Missense mutations were 1.5 times as likely to be pathogenic in the carboxy terminal of GLDC than in the amino-terminal part. Intragenic copy-number variations (CNVs) in GLDC were noted in 140 subjects, with biallelic CNVs present in 39 subjects. The position and frequency of the breakpoint for CNVs correlated with intron size and presence of Alu elements. Missense mutations, most often recurring, were the most common type of disease-causing mutation in AMT. Sequencing and CNV analysis identified biallelic pathogenic mutations in 98% of subjects. Based on genotype, 15% of subjects had an attenuated phenotype. The frequency of NKH is estimated at 1:76,000.

Conclusion: The 484 unique mutations now known in classic NKH provide a valuable overview for the development of genotype-based therapies.Genet Med 19 1, 104-111.
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http://dx.doi.org/10.1038/gim.2016.74DOI Listing
January 2017

Analysis of mutations within the intron20 splice donor site of CREBBP in patients with and without classical RSTS.

Eur J Hum Genet 2016 11 11;24(11):1639-1643. Epub 2016 May 11.

Department of Human Genetics, Leiden University Medical Centre, Leiden, The Netherlands.

Whole-exome sequencing of a patient with intellectual disability and without recognisable phenotype yielded a mutation in the intron20 splice donor site of CREBBP. Mutations at different positions within the same intron20 splice donor site were observed in three patients clinically suspected as having Rubinstein-Taybi syndrome (RSTS). All mutations were de novo and likely disease-causing. To investigate a putative difference in splicing between the patient without RSTS phenotype and the three patients with the RSTS phenotype, we analysed the effects of these mutations on splicing of the pre-mRNA of CREBBP. As no RNA of patients was available, we generated a new and improved exon-trap vector, pCDNAGHE, and tested the effect of the various mutations on splicing in vitro. All mutations lead to skipping of exon20. In one of the patients with an RSTS phenotype, there was also some normal splicing detectable. We conclude that the splicing pattern obtained by exon-trapping cannot explain the difference in phenotype between the patient without the RSTS phenotype and the patients with clinical RSTS. Patient or tissue-specific splice effects as well as modifying genes likely will explain the difference in phenotype.
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http://dx.doi.org/10.1038/ejhg.2016.47DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5110047PMC
November 2016

Association of MTOR Mutations With Developmental Brain Disorders, Including Megalencephaly, Focal Cortical Dysplasia, and Pigmentary Mosaicism.

JAMA Neurol 2016 07;73(7):836-845

Division of Genetic Medicine, Department of Pediatrics, University of Washington, Seattle, Washington, USA.

Importance: Focal cortical dysplasia (FCD), hemimegalencephaly, and megalencephaly constitute a spectrum of malformations of cortical development with shared neuropathologic features. These disorders are associated with significant childhood morbidity and mortality.

Objective: To identify the underlying molecular cause of FCD, hemimegalencephaly, and diffuse megalencephaly.

Design, Setting, And Participants: Patients with FCD, hemimegalencephaly, or megalencephaly (mean age, 11.7 years; range, 2-32 years) were recruited from Pediatric Hospital A. Meyer, the University of Hong Kong, and Seattle Children's Research Institute from June 2012 to June 2014. Whole-exome sequencing (WES) was performed on 8 children with FCD or hemimegalencephaly using standard-depth (50-60X) sequencing in peripheral samples (blood, saliva, or skin) from the affected child and their parents and deep (150-180X) sequencing in affected brain tissue. Targeted sequencing and WES were used to screen 93 children with molecularly unexplained diffuse or focal brain overgrowth. Histopathologic and functional assays of phosphatidylinositol 3-kinase-AKT (serine/threonine kinase)-mammalian target of rapamycin (mTOR) pathway activity in resected brain tissue and cultured neurons were performed to validate mutations.

Main Outcomes And Measures: Whole-exome sequencing and targeted sequencing identified variants associated with this spectrum of developmental brain disorders.

Results: Low-level mosaic mutations of MTOR were identified in brain tissue in 4 children with FCD type 2a with alternative allele fractions ranging from 0.012 to 0.086. Intermediate-level mosaic mutation of MTOR (p.Thr1977Ile) was also identified in 3 unrelated children with diffuse megalencephaly and pigmentary mosaicism in skin. Finally, a constitutional de novo mutation of MTOR (p.Glu1799Lys) was identified in 3 unrelated children with diffuse megalencephaly and intellectual disability. Molecular and functional analysis in 2 children with FCD2a from whom multiple affected brain tissue samples were available revealed a mutation gradient with an epicenter in the most epileptogenic area. When expressed in cultured neurons, all MTOR mutations identified here drive constitutive activation of mTOR complex 1 and enlarged neuronal size.

Conclusions And Relevance: In this study, mutations of MTOR were associated with a spectrum of brain overgrowth phenotypes extending from FCD type 2a to diffuse megalencephaly, distinguished by different mutations and levels of mosaicism. These mutations may be sufficient to cause cellular hypertrophy in cultured neurons and may provide a demonstration of the pattern of mosaicism in brain and substantiate the link between mosaic mutations of MTOR and pigmentary mosaicism in skin.
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http://dx.doi.org/10.1001/jamaneurol.2016.0363DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4979321PMC
July 2016

Transcription factor 7-like 1 is involved in hypothalamo-pituitary axis development in mice and humans.

Proc Natl Acad Sci U S A 2016 Feb 13;113(5):E548-57. Epub 2016 Jan 13.

Birth Defects Research Centre, Developmental Biology and Cancer Programme, University College London Institute of Child Health, London, WC1N 1EH, United Kingdom;

Aberrant embryonic development of the hypothalamus and/or pituitary gland in humans results in congenital hypopituitarism (CH). Transcription factor 7-like 1 (TCF7L1), an important regulator of the WNT/β-catenin signaling pathway, is expressed in the developing forebrain and pituitary gland, but its role during hypothalamo-pituitary (HP) axis formation or involvement in human CH remains elusive. Using a conditional genetic approach in the mouse, we first demonstrate that TCF7L1 is required in the prospective hypothalamus to maintain normal expression of the hypothalamic signals involved in the induction and subsequent expansion of Rathke's pouch progenitors. Next, we reveal that the function of TCF7L1 during HP axis development depends exclusively on the repressing activity of TCF7L1 and does not require its interaction with β-catenin. Finally, we report the identification of two independent missense variants in human TCF7L1, p.R92P and p.R400Q, in a cohort of patients with forebrain and/or pituitary defects. We demonstrate that these variants exhibit reduced repressing activity in vitro and in vivo relative to wild-type TCF7L1. Together, our data provide support for a conserved molecular function of TCF7L1 as a transcriptional repressor during HP axis development in mammals and identify variants in this transcription factor that are likely to contribute to the etiology of CH.
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http://dx.doi.org/10.1073/pnas.1503346113DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4747739PMC
February 2016

Recurrent De Novo Mutations Affecting Residue Arg138 of Pyrroline-5-Carboxylate Synthase Cause a Progeroid Form of Autosomal-Dominant Cutis Laxa.

Am J Hum Genet 2015 Sep 27;97(3):483-92. Epub 2015 Aug 27.

Institut fuer Medizinische Genetik und Humangenetik, Charité-Universitaetsmedizin Berlin, 13353 Berlin, Germany; FG Development & Disease, Max-Planck-Institut fuer Molekulare Genetik, 14195 Berlin, Germany; Berlin-Brandenburg Center for Regenerative Therapies, Charité-Universitaetsmedizin Berlin, 13353 Berlin, Germany. Electronic address:

Progeroid disorders overlapping with De Barsy syndrome (DBS) are collectively denoted as autosomal-recessive cutis laxa type 3 (ARCL3). They are caused by biallelic mutations in PYCR1 or ALDH18A1, encoding pyrroline-5-carboxylate reductase 1 and pyrroline-5-carboxylate synthase (P5CS), respectively, which both operate in the mitochondrial proline cycle. We report here on eight unrelated individuals born to non-consanguineous families clinically diagnosed with DBS or wrinkly skin syndrome. We found three heterozygous mutations in ALDH18A1 leading to amino acid substitutions of the same highly conserved residue, Arg138 in P5CS. A de novo origin was confirmed in all six probands for whom parental DNA was available. Using fibroblasts from affected individuals and heterologous overexpression, we found that the P5CS-p.Arg138Trp protein was stable and able to interact with wild-type P5CS but showed an altered sub-mitochondrial distribution. A reduced size upon native gel electrophoresis indicated an alteration of the structure or composition of P5CS mutant complex. Furthermore, we found that the mutant cells had a reduced P5CS enzymatic activity leading to a delayed proline accumulation. In summary, recurrent de novo mutations, affecting the highly conserved residue Arg138 of P5CS, cause an autosomal-dominant form of cutis laxa with progeroid features. Our data provide insights into the etiology of cutis laxa diseases and will have immediate impact on diagnostics and genetic counseling.
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http://dx.doi.org/10.1016/j.ajhg.2015.08.001DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4564990PMC
September 2015

De novo mutations in the motor domain of KIF1A cause cognitive impairment, spastic paraparesis, axonal neuropathy, and cerebellar atrophy.

Hum Mutat 2015 Jan 27;36(1):69-78. Epub 2014 Nov 27.

Biomedical Proteomics Research Center, Korea Research Institute of Bioscience and Biotechnology, Daejeon, Korea.

KIF1A is a neuron-specific motor protein that plays important roles in cargo transport along neurites. Recessive mutations in KIF1A were previously described in families with spastic paraparesis or sensory and autonomic neuropathy type-2. Here, we report 11 heterozygous de novo missense mutations (p.S58L, p.T99M, p.G102D, p.V144F, p.R167C, p.A202P, p.S215R, p.R216P, p.L249Q, p.E253K, and p.R316W) in KIF1A in 14 individuals, including two monozygotic twins. Two mutations (p.T99M and p.E253K) were recurrent, each being found in unrelated cases. All these de novo mutations are located in the motor domain (MD) of KIF1A. Structural modeling revealed that they alter conserved residues that are critical for the structure and function of the MD. Transfection studies suggested that at least five of these mutations affect the transport of the MD along axons. Individuals with de novo mutations in KIF1A display a phenotype characterized by cognitive impairment and variable presence of cerebellar atrophy, spastic paraparesis, optic nerve atrophy, peripheral neuropathy, and epilepsy. Our findings thus indicate that de novo missense mutations in the MD of KIF1A cause a phenotype that overlaps with, while being more severe, than that associated with recessive mutations in the same gene.
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http://dx.doi.org/10.1002/humu.22709DOI Listing
January 2015

Clinical characterization, genetic mapping and whole-genome sequence analysis of a novel autosomal recessive intellectual disability syndrome.

Eur J Med Genet 2014 Oct 29;57(10):543-51. Epub 2014 Jul 29.

Department of Medical Genetics, Genome-Scale Biology Research Program, University of Helsinki and Haartman Institute, Helsinki, Finland. Electronic address:

We identified six patients presenting with a strikingly similar clinical phenotype of profound syndromic intellectual disability of unknown etiology. All patients lived in the same village. Extensive genealogical work revealed that the healthy parents of the patients were all distantly related to a common ancestor from the 17th century, suggesting autosomal recessive inheritance. In addition to intellectual disability, the clinical features included hypotonia, strabismus, difficulty to fix the eyes to an object, planovalgus in the feet, mild contractures in elbow joints, interphalangeal joint hypermobility and coarse facial features that develop gradually during childhood. The clinical phenotype did not fit any known syndrome. Genome-wide SNP genotyping of the patients and genetic mapping revealed the longest shared homozygosity at 3p22.1-3p21.1 encompassing 11.5 Mb, with no other credible candidate loci emerging. Single point parametric linkage analysis showed logarithm of the odds score of 11 for the homozygous region, thus identifying a novel intellectual disability predisposition locus. Whole-genome sequencing of one affected individual pinpointed three genes with potentially protein damaging homozygous sequence changes within the predisposition locus: transketolase (TKT), prolyl 4-hydroxylase transmembrane (P4HTM), and ubiquitin specific peptidase 4 (USP4). The changes were found in heterozygous form with 0.3-0.7% allele frequencies in 402 whole-genome sequenced controls from the north-east of Finland. No homozygotes were found in this nor additional control data sets. Our study facilitates clinical and molecular diagnosis of patients with this novel autosomal recessive intellectual disability syndrome. However, further studies are needed to unambiguously identify the underlying genetic defect.
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http://dx.doi.org/10.1016/j.ejmg.2014.07.002DOI Listing
October 2014

Report of interstitial 22q13.1q13.2 microduplication in two siblings with distinctive dysmorphic features, heart defect and mental retardation.

Eur J Med Genet 2013 Jul 22;56(7):389-96. Epub 2013 May 22.

Department of Clinical Genetics, Oulu University Hospital, University of Oulu, Oulu, Finland.

We present two siblings (a boy and a girl) with a submicroscopic 4 Mb duplication at 22q13.1q13.2. Both children manifested infantile hypotonia and delayed motor milestones, congenital heart defect, growth deficiency, and strikingly similar and distinctive craniofacial dysmorphism including brachycephaly, blepharophimosis, short broad-based nose and wide mouth with thin upper lip. The boy had also a submucous cleft palate. Both had fair skin and hair compared with their parents. Both had moderate mental retardation associated with a short attention span. A 4-Mb interstitial duplication at 22q13.1q13.2 was detected by whole genome microarray comparative genomic hybridisation (array CGH) in both children. The duplication was confirmed by fluorescence in situ hybridisation (FISH) analysis. Their parents had normal array CGH results. FISH analysis revealed that the father was a carrier of a balanced interchromosomal submicroscopic insertion of 22q13 into chromosome 11q23, explaining the unbalanced aberration detected in both children. This report narrows down the critical region at 22q13.1q13.2, which is associated with mental retardation, pre- and post-natal growth retardation, hippocampal malformation, psychiatric symptoms such as short attention span and facial dysmorphism including hypertelorism, epicanthal folds and low set/abnormal ears.
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http://dx.doi.org/10.1016/j.ejmg.2013.05.004DOI Listing
July 2013

The SETX missense variation spectrum as evaluated in patients with ALS4-like motor neuron diseases.

Neurogenetics 2013 Feb 6;14(1):53-61. Epub 2012 Nov 6.

Department of Human Genetics, Ruhr University, 44780 Bochum, Germany.

Mutations in the senataxin (SETX) gene can cause amyotrophic lateral sclerosis 4 (ALS4), an autosomal dominant form of juvenile onset amyotrophic lateral sclerosis, or result in autosomal recessive ataxia with oculomotor apraxia type 2. Great caution regarding the possible disease causation, especially of missense variations, has to be taken. Here, we evaluated the significance of all previously reported SETX missense mutations as well as six newly identified variations in 54 patients suspected of having ALS4. Yet, epidemiologic and in silico evidence indicates that all newly identified variations and two previously published ALS4-related missense variations (C1554G and I2547T) are most likely non-pathogenic, demonstrating the problems of interpretation of SETX missense alleles in the absence of functional assays.
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http://dx.doi.org/10.1007/s10048-012-0347-4DOI Listing
February 2013