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1.
Clin Genet ; 2020 Oct 03.
Artigo em Inglês | MEDLINE | ID: mdl-33009664

RESUMO

The gamma-1 isoform of casein kinase 1, the protein encoded by CSNK1G1, is involved in the growth and morphogenesis of cells. This protein is expressed ubiquitously among many tissue types, including the brain, where it regulates the phosphorylation of N-methyl-D-aspartate receptors and plays a role in synaptic transmission. One prior individual with a de novo variant in CSNK1G presenting with severe developmental delay and early-onset epilepsy has been reported. Here we report an updated clinical history of this previously published case, as well as four additional individuals with de novo variants in CSNK1G1 identified via microarray-based comparative genomic hybridization, exome, or genome sequencing. All individuals (n = 5) had developmental delay. At least three individuals had diagnoses of autism spectrum disorder. All participants were noted to have dysmorphic facial features, although the reported findings varied widely and therefore may not clearly be recognizable. None of the participants had additional major malformations. Taken together, our data suggest that CSNK1G1 may be a cause of syndromic developmental delay and possibly autism spectrum disorder.

2.
Hum Mol Genet ; 2020 Oct 19.
Artigo em Inglês | MEDLINE | ID: mdl-33073849

RESUMO

MPP5 is a highly conserved apical complex protein essential for cell polarity, fate and survival. Defects in cell polarity are associated with neurologic disorders including autism and microcephaly. MPP5 is essential for neurogenesis in animal models, but human variants leading to neurologic impairment have not been described. We identified three patients with heterozygous MPP5 de novo variants (DNV) and global developmental delay (GDD), and compared their phenotypes and MRIs to ascertain how MPP5 DNV lead to GDD. All three patients with MPP5 DNV experienced GDD with language delay/regression and behavioral changes. MRIs ranged from normal to decreased gyral folding and microcephaly. The effects of MPP5 depletion on developing brain was assessed by creating a heterozygous (het) murine model with CNS-specific nestin-Cre drivers (het CKO). In the het CKO model, Mpp5 depletion led to microcephaly, decreased cerebellar volume and cortical thickness. Het CKO mice had decreased ependymal cells and Mpp5 at the apical surface of cortical ventricular zone compared to wild type. Het CKO mice also failed to maintain progenitor pools essential for neurogenesis. The proportion of cortical cells undergoing apoptotic cell death increased, suggesting that cell death reduces progenitor population and neuron number. Het CKO mice also showed behavioral changes, similar to our patients. To our knowledge, this is the first report to show that variants in MPP5 are associated with GDD, behavioral abnormalities and language regression/delay. Murine modeling shows that neurogenesis is likely altered in these individuals, with cell death and skewed cellular composition playing significant roles.

3.
J Child Neurol ; : 883073820953001, 2020 Sep 15.
Artigo em Inglês | MEDLINE | ID: mdl-32928027

RESUMO

OBJECTIVE: To describe a founder mutation effect and the clinical phenotype of homozygous FRRS1L c.737_739delGAG (p.Gly246del) variant in 15 children of Puerto Rican (Boricua) ancestry presenting with early infantile epileptic encephalopathy (EIEE-37) with prominent movement disorder. BACKGROUND: EIEE-37 is caused by biallelic loss of function variants in the FRRS1L gene, which is critical for AMPA-receptor function, resulting in intractable epilepsy and dyskinesia. METHODS: A retrospective, multicenter chart review of patients sharing the same homozygous FRRS1L (p.Gly246del) pathogenic variant identified by clinical genetic testing. Clinical information was collected regarding neurodevelopmental outcomes, neuroimaging, electrographic features and clinical response to antiseizure medications. RESULTS: Fifteen patients from 12 different families of Puerto Rican ancestry were homozygous for the FRRS1L (p.Gly246del) pathogenic variant, with ages ranging from 1 to 25 years. The onset of seizures was from 6 to 24 months. All had hypotonia, severe global developmental delay, and most had hyperkinetic involuntary movements. Developmental regression during the first year of life was common (86%). Electroencephalogram showed hypsarrhythmia in 66% (10/15), with many older children evolving into Lennox-Gastaut syndrome. Six patients demonstrated progressive volume loss and/or cerebellar atrophy on brain magnetic resonance imaging (MRI). CONCLUSIONS: We describe the largest cohort to date of patients with epileptic encephalopathy. We estimate that 0.76% of unaffected individuals of Puerto Rican ancestry carry this pathogenic variant due to a founder effect. Children homozygous for the FRRS1L (p.Gly246del) Boricua variant exhibit a very homogenous phenotype of early developmental regression and epilepsy, starting with infantile spasms and evolving into Lennox-Gastaut syndrome with hyperkinetic movement disorder.

4.
Nat Commun ; 11(1): 3698, 2020 07 23.
Artigo em Inglês | MEDLINE | ID: mdl-32703943

RESUMO

Intellectual disability (ID) is a heterogeneous clinical entity and includes an excess of males who harbor variants on the X-chromosome (XLID). We report rare FAM50A missense variants in the original Armfield XLID syndrome family localized in Xq28 and four additional unrelated males with overlapping features. Our fam50a knockout (KO) zebrafish model exhibits abnormal neurogenesis and craniofacial patterning, and in vivo complementation assays indicate that the patient-derived variants are hypomorphic. RNA sequencing analysis from fam50a KO zebrafish show dysregulation of the transcriptome, with augmented spliceosome mRNAs and depletion of transcripts involved in neurodevelopment. Zebrafish RNA-seq datasets show a preponderance of 3' alternative splicing events in fam50a KO, suggesting a role in the spliceosome C complex. These data are supported with transcriptomic signatures from cell lines derived from affected individuals and FAM50A protein-protein interaction data. In sum, Armfield XLID syndrome is a spliceosomopathy associated with aberrant mRNA processing during development.


Assuntos
Proteínas de Ligação a DNA/genética , Deficiência Intelectual/genética , Retardo Mental Ligado ao Cromossomo X/genética , Mutação/genética , Proteínas de Ligação a RNA/genética , Spliceossomos/metabolismo , Proteínas de Peixe-Zebra/genética , Adulto , Animais , Núcleo Celular/metabolismo , Criança , Pré-Escolar , Família , Feminino , Regulação da Expressão Gênica no Desenvolvimento , Humanos , Masculino , Camundongos , Mutação de Sentido Incorreto/genética , Células NIH 3T3 , Linhagem , Fenótipo , Transporte Proteico , Processamento de RNA/genética , RNA Mensageiro/genética , RNA Mensageiro/metabolismo , RNA Nuclear Pequeno/genética , Síndrome , Peixe-Zebra/genética , Proteínas de Peixe-Zebra/metabolismo
5.
Am J Hum Genet ; 107(3): 544-554, 2020 09 03.
Artigo em Inglês | MEDLINE | ID: mdl-32730804

RESUMO

RNA polymerase II interacts with various other complexes and factors to ensure correct initiation, elongation, and termination of mRNA transcription. One of these proteins is SR-related CTD-associated factor 4 (SCAF4), which is important for correct usage of polyA sites for mRNA termination. Using exome sequencing and international matchmaking, we identified nine likely pathogenic germline variants in SCAF4 including two splice-site and seven truncating variants, all residing in the N-terminal two thirds of the protein. Eight of these variants occurred de novo, and one was inherited. Affected individuals demonstrated a variable neurodevelopmental disorder characterized by mild intellectual disability, seizures, behavioral abnormalities, and various skeletal and structural anomalies. Paired-end RNA sequencing on blood lymphocytes of SCAF4-deficient individuals revealed a broad deregulation of more than 9,000 genes and significant differential splicing of more than 2,900 genes, indicating an important role of SCAF4 in mRNA processing. Knockdown of the SCAF4 ortholog CG4266 in the model organism Drosophila melanogaster resulted in impaired locomotor function, learning, and short-term memory. Furthermore, we observed an increased number of active zones in larval neuromuscular junctions, representing large glutamatergic synapses. These observations indicate a role of CG4266 in nervous system development and function and support the implication of SCAF4 in neurodevelopmental phenotypes. In summary, our data show that heterozygous, likely gene-disrupting variants in SCAF4 are causative for a variable neurodevelopmental disorder associated with impaired mRNA processing.


Assuntos
Deficiência Intelectual/genética , Transtornos do Neurodesenvolvimento/genética , Convulsões/genética , Fatores de Processamento de Serina-Arginina/genética , Animais , Criança , Drosophila melanogaster/genética , Feminino , Técnicas de Silenciamento de Genes , Variação Genética/genética , Heterozigoto , Humanos , Deficiência Intelectual/fisiopatologia , Locomoção/genética , Masculino , Mutação/genética , Transtornos do Neurodesenvolvimento/fisiopatologia , RNA Polimerase II/genética , Processamento Pós-Transcricional do RNA/genética , RNA Mensageiro/genética , Convulsões/fisiopatologia , Sequenciamento Completo do Exoma
6.
Am J Med Genet A ; 182(9): 2037-2048, 2020 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-32710489

RESUMO

The SET domain containing 2, histone lysine methyltransferase encoded by SETD2 is a dual-function methyltransferase for histones and microtubules and plays an important role for transcriptional regulation, genomic stability, and cytoskeletal functions. Specifically, SETD2 is associated with trimethylation of histone H3 at lysine 36 (H3K36me3) and methylation of α-tubulin at lysine 40. Heterozygous loss of function and missense variants have previously been described with Luscan-Lumish syndrome (LLS), which is characterized by overgrowth, neurodevelopmental features, and absence of overt congenital anomalies. We have identified 15 individuals with de novo variants in codon 1740 of SETD2 whose features differ from those with LLS. Group 1 consists of 12 individuals with heterozygous variant c.5218C>T p.(Arg1740Trp) and Group 2 consists of 3 individuals with heterozygous variant c.5219G>A p.(Arg1740Gln). The phenotype of Group 1 includes microcephaly, profound intellectual disability, congenital anomalies affecting several organ systems, and similar facial features. Individuals in Group 2 had moderate to severe intellectual disability, low normal head circumference, and absence of additional major congenital anomalies. While LLS is likely due to loss of function of SETD2, the clinical features seen in individuals with variants affecting codon 1740 are more severe suggesting an alternative mechanism, such as gain of function, effects on epigenetic regulation, or posttranslational modification of the cytoskeleton. Our report is a prime example of different mutations in the same gene causing diverging phenotypes and the features observed in Group 1 suggest a new clinically recognizable syndrome uniquely associated with the heterozygous variant c.5218C>T p.(Arg1740Trp) in SETD2.

7.
Am J Hum Genet ; 107(1): 164-172, 2020 07 02.
Artigo em Inglês | MEDLINE | ID: mdl-32553196

RESUMO

CNOT1 is a member of the CCR4-NOT complex, which is a master regulator, orchestrating gene expression, RNA deadenylation, and protein ubiquitination. We report on 39 individuals with heterozygous de novo CNOT1 variants, including missense, splice site, and nonsense variants, who present with a clinical spectrum of intellectual disability, motor delay, speech delay, seizures, hypotonia, and behavioral problems. To link CNOT1 dysfunction to the neurodevelopmental phenotype observed, we generated variant-specific Drosophila models, which showed learning and memory defects upon CNOT1 knockdown. Introduction of human wild-type CNOT1 was able to rescue this phenotype, whereas mutants could not or only partially, supporting our hypothesis that CNOT1 impairment results in neurodevelopmental delay. Furthermore, the genetic interaction with autism-spectrum genes, such as ASH1L, DYRK1A, MED13, and SHANK3, was impaired in our Drosophila models. Molecular characterization of CNOT1 variants revealed normal CNOT1 expression levels, with both mutant and wild-type alleles expressed at similar levels. Analysis of protein-protein interactions with other members indicated that the CCR4-NOT complex remained intact. An integrated omics approach of patient-derived genomics and transcriptomics data suggested only minimal effects on endonucleolytic nonsense-mediated mRNA decay components, suggesting that de novo CNOT1 variants are likely haploinsufficient hypomorph or neomorph, rather than dominant negative. In summary, we provide strong evidence that de novo CNOT1 variants cause neurodevelopmental delay with a wide range of additional co-morbidities. Whereas the underlying pathophysiological mechanism warrants further analysis, our data demonstrate an essential and central role of the CCR4-NOT complex in human brain development.


Assuntos
Deficiências do Desenvolvimento/genética , Expressão Gênica/genética , Transtornos do Neurodesenvolvimento/genética , Membro 2 do Grupo A da Subfamília 4 de Receptores Nucleares/genética , RNA/genética , Receptores CCR4/genética , Fatores de Transcrição/genética , Alelos , Feminino , Variação Genética/genética , Haploinsuficiência/genética , Heterozigoto , Humanos , Masculino , Malformações do Sistema Nervoso/genética , Fenótipo , Estabilidade Proteica
8.
Nat Commun ; 11(1): 2441, 2020 05 15.
Artigo em Inglês | MEDLINE | ID: mdl-32415109

RESUMO

KIF21B is a kinesin protein that promotes intracellular transport and controls microtubule dynamics. We report three missense variants and one duplication in KIF21B in individuals with neurodevelopmental disorders associated with brain malformations, including corpus callosum agenesis (ACC) and microcephaly. We demonstrate, in vivo, that the expression of KIF21B missense variants specifically recapitulates patients' neurodevelopmental abnormalities, including microcephaly and reduced intra- and inter-hemispheric connectivity. We establish that missense KIF21B variants impede neuronal migration through attenuation of kinesin autoinhibition leading to aberrant KIF21B motility activity. We also show that the ACC-related KIF21B variant independently perturbs axonal growth and ipsilateral axon branching through two distinct mechanisms, both leading to deregulation of canonical kinesin motor activity. The duplication introduces a premature termination codon leading to nonsense-mediated mRNA decay. Although we demonstrate that Kif21b haploinsufficiency leads to an impaired neuronal positioning, the duplication variant might not be pathogenic. Altogether, our data indicate that impaired KIF21B autoregulation and function play a critical role in the pathogenicity of human neurodevelopmental disorder.


Assuntos
Cinesina/genética , Atividade Motora , Mutação/genética , Transtornos do Neurodesenvolvimento/genética , Transtornos do Neurodesenvolvimento/fisiopatologia , Animais , Axônios/metabolismo , Movimento Celular , Proliferação de Células , Córtex Cerebral/embriologia , Córtex Cerebral/patologia , Córtex Cerebral/fisiopatologia , Feminino , Regulação da Expressão Gênica no Desenvolvimento , Células HEK293 , Humanos , Masculino , Camundongos , Mutação de Sentido Incorreto/genética , Rede Nervosa/patologia , Rede Nervosa/fisiopatologia , Neurônios/metabolismo , Tamanho do Órgão , Organogênese/genética , Linhagem , RNA Mensageiro/genética , RNA Mensageiro/metabolismo , Peixe-Zebra/anatomia & histologia , Peixe-Zebra/genética
9.
Mol Psychiatry ; 2020 Apr 28.
Artigo em Inglês | MEDLINE | ID: mdl-32346159

RESUMO

Defects in histone methyltransferases (HMTs) are major contributing factors in neurodevelopmental disorders (NDDs). Heterozygous variants of SETD1A involved in histone H3 lysine 4 (H3K4) methylation were previously identified in individuals with schizophrenia. Here, we define the clinical features of the Mendelian syndrome associated with haploinsufficiency of SETD1A by investigating 15 predominantly pediatric individuals who all have de novo SETD1A variants. These individuals present with a core set of symptoms comprising global developmental delay and/or intellectual disability, subtle facial dysmorphisms, behavioral and psychiatric problems. We examined cellular phenotypes in three patient-derived lymphoblastoid cell lines with three variants: p.Gly535Alafs*12, c.4582-2_4582delAG, and p.Tyr1499Asp. These patient cell lines displayed DNA damage repair defects that were comparable to previously observed RNAi-mediated depletion of SETD1A. This suggested that these variants, including the p.Tyr1499Asp in the catalytic SET domain, behave as loss-of-function (LoF) alleles. Previous studies demonstrated a role for SETD1A in cell cycle control and differentiation. However, individuals with SETD1A variants do not show major structural brain defects or severe microcephaly, suggesting that defective proliferation and differentiation of neural progenitors is unlikely the single underlying cause of the disorder. We show here that the Drosophila melanogaster SETD1A orthologue is required in postmitotic neurons of the fly brain for normal memory, suggesting a role in post development neuronal function. Together, this study defines a neurodevelopmental disorder caused by dominant de novo LoF variants in SETD1A and further supports a role for H3K4 methyltransferases in the regulation of neuronal processes underlying normal cognitive functioning.

10.
J Med Genet ; 57(10): 717-724, 2020 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-32152250

RESUMO

BACKGROUND: Rare variants in hundreds of genes have been implicated in developmental delay (DD), intellectual disability (ID) and neurobehavioural phenotypes. TNRC6B encodes a protein important for RNA silencing. Heterozygous truncating variants have been reported in three patients from large cohorts with autism, but no full phenotypic characterisation was described. METHODS: Clinical and molecular characterisation was performed on 17 patients with TNRC6B variants. Clinical data were obtained by retrospective chart review, parent interviews, direct patient interaction with providers and formal neuropsychological evaluation. RESULTS: Clinical findings included DD/ID (17/17) (speech delay in 94% (16/17), fine motor delay in 82% (14/17) and gross motor delay in 71% (12/17) of subjects), autism or autistic traits (13/17), attention deficit and hyperactivity disorder (ADHD) (11/17), other behavioural problems (7/17) and musculoskeletal findings (12/17). Other congenital malformations or clinical findings were occasionally documented. The majority of patients exhibited some dysmorphic features but no recognisable gestalt was identified. 17 heterozygous TNRC6B variants were identified in 12 male and five female unrelated subjects by exome sequencing (14), a targeted panel (2) and a chromosomal microarray (1). The variants were nonsense (7), frameshift (5), splice site (2), intragenic deletions (2) and missense (1). CONCLUSIONS: Variants in TNRC6B cause a novel genetic disorder characterised by recurrent neurocognitive and behavioural phenotypes featuring DD/ID, autism, ADHD and other behavioural abnormalities. Our data highly suggest that haploinsufficiency is the most likely pathogenic mechanism. TNRC6B should be added to the growing list of genes of the RNA-induced silencing complex associated with ID/DD, autism and ADHD.

11.
Neuron ; 106(2): 246-255.e6, 2020 04 22.
Artigo em Inglês | MEDLINE | ID: mdl-32097629

RESUMO

Genes mutated in human neuronal migration disorders encode tubulin proteins and a variety of tubulin-binding and -regulating proteins, but it is very poorly understood how these proteins function together to coordinate migration. Additionally, the way in which regional differences in neocortical migration are controlled is completely unknown. Here we describe a new syndrome with remarkably region-specific effects on neuronal migration in the posterior cortex, reflecting de novo variants in CEP85L. We show that CEP85L is required cell autonomously in vivo and in vitro for migration, that it localizes to the maternal centriole, and that it forms a complex with many other proteins required for migration, including CDK5, LIS1, NDE1, KIF2A, and DYNC1H1. Loss of CEP85L disrupts CDK5 localization and activation, leading to centrosome disorganization and disrupted microtubule cytoskeleton organization. Together, our findings suggest that CEP85L highlights a complex that controls CDK5 activity to promote neuronal migration.


Assuntos
Movimento Celular , Quinase 5 Dependente de Ciclina/genética , Proteínas do Citoesqueleto/genética , Lisencefalia/genética , Lisencefalia/patologia , Neocórtex/patologia , Neurônios/patologia , Proteínas de Fusão Oncogênica/genética , Centríolos/genética , Criança , Pré-Escolar , Feminino , Humanos , Masculino , Microtúbulos/genética , Microtúbulos/ultraestrutura , Proteínas do Tecido Nervoso/fisiologia , Adulto Jovem
12.
Sci Adv ; 6(4): eaax0021, 2020 01.
Artigo em Inglês | MEDLINE | ID: mdl-32010779

RESUMO

Lysine acetyltransferase 6A (KAT6A) and its paralog KAT6B form stoichiometric complexes with bromodomain- and PHD finger-containing protein 1 (BRPF1) for acetylation of histone H3 at lysine 23 (H3K23). We report that these complexes also catalyze H3K23 propionylation in vitro and in vivo. Immunofluorescence microscopy and ATAC-See revealed the association of this modification with active chromatin. Brpf1 deletion obliterates the acylation in mouse embryos and fibroblasts. Moreover, we identify BRPF1 variants in 12 previously unidentified cases of syndromic intellectual disability and demonstrate that these cases and known BRPF1 variants impair H3K23 propionylation. Cardiac anomalies are present in a subset of the cases. H3K23 acylation is also impaired by cancer-derived somatic BRPF1 mutations. Valproate, vorinostat, propionate and butyrate promote H3K23 acylation. These results reveal the dual functionality of BRPF1-KAT6 complexes, shed light on mechanisms underlying related developmental disorders and various cancers, and suggest mutation-based therapy for medical conditions with deficient histone acylation.


Assuntos
Proteínas Adaptadoras de Transdução de Sinal/metabolismo , Proteínas de Ligação a DNA/metabolismo , Histona Acetiltransferases/metabolismo , Histonas/metabolismo , Neoplasias/etiologia , Neoplasias/metabolismo , Transtornos do Neurodesenvolvimento/etiologia , Transtornos do Neurodesenvolvimento/metabolismo , Acetilação , Proteínas Adaptadoras de Transdução de Sinal/genética , Sequência de Aminoácidos , Animais , Encéfalo/anormalidades , Encéfalo/diagnóstico por imagem , Linhagem Celular , Análise Mutacional de DNA , Proteínas de Ligação a DNA/genética , Suscetibilidade a Doenças , Predisposição Genética para Doença , Histona Acetiltransferases/genética , Humanos , Imagem por Ressonância Magnética , Camundongos , Camundongos Knockout , Modelos Biológicos , Complexos Multiproteicos/metabolismo , Mutação , Neoplasias/diagnóstico , Transtornos do Neurodesenvolvimento/diagnóstico , Fenótipo , Ligação Proteica , Domínios e Motivos de Interação entre Proteínas , Processamento de Proteína Pós-Traducional , Síndrome
13.
Am J Hum Genet ; 106(2): 234-245, 2020 02 06.
Artigo em Inglês | MEDLINE | ID: mdl-31928709

RESUMO

Germline pathogenic variants in chromatin-modifying enzymes are a common cause of pediatric developmental disorders. These enzymes catalyze reactions that regulate epigenetic inheritance via histone post-translational modifications and DNA methylation. Cytosine methylation (5-methylcytosine [5mC]) of DNA is the quintessential epigenetic mark, yet no human Mendelian disorder of DNA demethylation has yet been delineated. Here, we describe in detail a Mendelian disorder caused by the disruption of DNA demethylation. TET3 is a methylcytosine dioxygenase that initiates DNA demethylation during early zygote formation, embryogenesis, and neuronal differentiation and is intolerant to haploinsufficiency in mice and humans. We identify and characterize 11 cases of human TET3 deficiency in eight families with the common phenotypic features of intellectual disability and/or global developmental delay; hypotonia; autistic traits; movement disorders; growth abnormalities; and facial dysmorphism. Mono-allelic frameshift and nonsense variants in TET3 occur throughout the coding region. Mono-allelic and bi-allelic missense variants localize to conserved residues; all but one such variant occur within the catalytic domain, and most display hypomorphic function in an assay of catalytic activity. TET3 deficiency and other Mendelian disorders of the epigenetic machinery show substantial phenotypic overlap, including features of intellectual disability and abnormal growth, underscoring shared disease mechanisms.


Assuntos
Desmetilação do DNA , Deficiências do Desenvolvimento/genética , Deficiências do Desenvolvimento/patologia , Dioxigenases/deficiência , Adulto , Sequência de Aminoácidos , Transtorno Autístico/genética , Transtorno Autístico/patologia , Criança , Pré-Escolar , Dioxigenases/química , Dioxigenases/genética , Desenvolvimento Embrionário , Feminino , Regulação da Expressão Gênica no Desenvolvimento , Transtornos do Crescimento/genética , Transtornos do Crescimento/patologia , Humanos , Lactente , Masculino , Pessoa de Meia-Idade , Transtornos dos Movimentos/genética , Transtornos dos Movimentos/patologia , Linhagem , Conformação Proteica , Homologia de Sequência , Adulto Jovem
15.
Artigo em Inglês | MEDLINE | ID: mdl-31953988

RESUMO

In 2011, KIAA1033/WASHC4 was associated with autosomal recessive intellectual disability (ARID) in a large consanguineous family comprising seven affected individuals with moderate ID and short stature. Since then, no other cases of KIAA1033 variants have been reported. Here we describe three additional patients (from two unrelated families) with syndromic ID due to compound heterozygous KIAA1033 variants ascertained by exome sequencing (ES). Two sisters, aged 4 and 5.5 years, had a stop-gain and a missense variants, each inherited from one parent (p.(Gln442*) and p.(Asp1048Gly)). Both had learning disabilities, macrocephaly, dysmorphic features, skeletal anomalies, and subependymal heterotopic nodules. In addition, the younger sibling had a congenital absence of the right internal carotid and bilateral sensorineural hearing loss. The third patient was aged 34 years and had two missense variants, one inherited from each parent (p.(Lys1079Arg) and p.(His503Arg)). This patient presented with mild ID, short stature, and microcephaly. KIAA1033 encodes a large protein (WASHC4), which is part of the WASH complex. The WASH complex is involved in the regulation of the fission of tubules that serve as transport intermediates during endosome sorting. Another member of the WASH complex, KIAA0196/WASHC5, has already been implicated in ARID with brain and cardiac malformations, under the designation of 3C or Ritscher-Schinzel syndrome (MIM#20210). ES has proved efficient for finding replications of genes with insufficient data in the literature to be defined as new OMIM genes. We conclude that KIAA1033 is responsible for a heterogeneous ARID phenotype, and additional description will be needed to refine the clinical phenotype.

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