ARHGEF9 disease

Objective:We aimed to generate a review and description of the phenotypic and genotypic spectra of ARHGEF9 mutations.Methods:Patients with mutations or chromosomal disruptions affecting ARHGEF9 were identified through our clinics and review of the literature. Detailed medical history and examination findings were obtained via a standardized questionnaire, or if this was not possible by reviewing the published phenotypic features.Results:A total of 18 patients (including 5 females) were identified. Six had de novo, 5 had maternally inherited mutations, and 7 had chromosomal disruptions. All females had strongly skewed X-inactivation in favor of the abnormal X-chromosome. Symptoms presented in early childhood with delayed motor development alone or in combination with seizures. Intellectual disability was severe in most and moderate in patients with milder mutations. Males with severe intellectual disability had severe, often intractable, epilepsy and exhibited a particular facial dysmorphism. Patients with mutations in exon 9 affecting the protein's PH domain did not develop epilepsy.Conclusions:ARHGEF9 encodes a crucial neuronal synaptic protein; loss of function of which results in severe intellectual disability, epilepsy, and a particular facial dysmorphism. Loss of only the protein's PH domain function is associated with the absence of epilepsy.

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Clinical, genetic, and molecular characterization of hyperphosphatasia with mental retardation: a case report and literature review

Diagnostic Pathology ◽

10.1186/s13000-019-0902-5 ◽

2019 ◽

Vol 14 (1) ◽

Cited By ~ 2

Author(s):

Layal Abi Farraj ◽

Wassim Daoud Khatoun ◽

Naji Abou Chebel ◽

Victor Wakim ◽

Katia Dawali ◽

...

Keyword(s):

Alkaline Phosphatase ◽

Mental Retardation ◽

Intellectual Disability ◽

Developmental Delay ◽

Novel Mutation ◽

Blood Levels ◽

Facial Dysmorphism ◽

Loss Of Function ◽

Clinical Genetic ◽

Severe Intellectual Disability

Abstract Background Hyperphosphatasia with mental retardation syndrome (HPMRS) is a recessive disorder characterized by high blood levels of alkaline phosphatase together with typical dysmorphic signs such as cleft palate, intellectual disability, cardiac abnormalities, and developmental delay. Genes involved in the glycosylphosphatidylinositol pathway and known to be mutated in HPMRS have never been characterized in the Lebanese population. Case presentation Herein, we describe a pair of monozygotic twins presenting with severe intellectual disability, distinct facial dysmorphism, developmental delay, and increased alkaline phosphatase level. Two individuals underwent whole exome sequencing followed by Sanger sequencing to confirm the co-segregation of the mutation in the consanguineous family. A biallelic loss of function mutation in PGAP3 was detected. Both patients were homozygous for the c.203delC (p.C68LfsX88) mutation and the parents were carriers confirming the founder effect of the mutation. High ALP serum levels confirmed the molecular diagnosis. Conclusion Our findings have illustrated the genomic profile of PGAP3-related HPMRS which is essential for targeted molecular and genetic testing. Moreover, we found previously unreported clinical findings such as hypodontia and skin hyperpigmentation. These features, together with the novel mutation expand the phenotypic and genotypic spectrum of this rare recessive disorder.

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A novel de novo hemizygous ARHGEF9 mutation associated with severe intellectual disability and epilepsy: a case report

Journal of International Medical Research ◽

10.1177/03000605211058372 ◽

2021 ◽

Vol 49 (11) ◽

pp. 030006052110583

Author(s):

Tong Qiu ◽

Qian Dai ◽

Qiu Wang

Keyword(s):

Intellectual Disability ◽

Exome Sequencing ◽

Developmental Delay ◽

De Novo ◽

Clinical Symptoms ◽

Genetic Diagnosis ◽

Epileptic Seizures ◽

Autism Spectrum ◽

Loss Of Function ◽

Severe Intellectual Disability

ARHGEF9 encodes collybistin, a brain-specific guanosine diphosphate-guanosine-5′-triphosphate exchange factor that plays an important role in clustering of gephyrin and γ-aminobutyric acid type A receptors in the postsynaptic membrane. Overwhelming evidence suggests that defects in this protein can cause X-linked intellectual disability, which comprises a series of clinical phenotypes, including autism spectrum disorder, behavior disorder, intellectual disability, and febrile seizures. Here, we report a boy with clinical symptoms of severe intellectual disability, epilepsy, and developmental delay and regression. Trio exome sequencing ( trio-clinical exome sequencing) identified a novel hemizygous deletion, c.656_c.669delACTTCTTTGAGGCC (p. His219Leu fs*9), in exon 5 of ARHGEF9. This variant was not reported in either the Genome Aggregation Database or our database of 309 patients with neurodevelopmental disorders. Oxcarbazepine and levetiracetam reduced the frequency of the patient’s epileptic seizures to a certain extent, but psychomotor developmental delay and developmental regression became more obvious with age. This case study seeks to report a de novo loss-of-function mutation of ARHGEF9, aiming to emphasize the genetic diagnosis of X-linked intellectual disability and further improve knowledge of the ethnic distribution of ARHGEF9 mutations.

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The first familial NSD2 cases with a novel variant in a Chinese father and daughter with atypical WHS facial features and a 7.5-year follow-up of growth hormone therapy

BMC Medical Genomics ◽

10.1186/s12920-020-00831-9 ◽

2020 ◽

Vol 13 (1) ◽

Author(s):

Xuyun Hu ◽

Di Wu ◽

Yuchuan Li ◽

Liya Wei ◽

Xiaoqiao Li ◽

...

Keyword(s):

Growth Hormone ◽

Intellectual Disability ◽

Hormone Therapy ◽

De Novo ◽

Growth Hormone Therapy ◽

Chinese Family ◽

Facial Dysmorphism ◽

Facial Features ◽

Loss Of Function ◽

Genomic Disorder

Abstract Background Wolf-Hirschhorn syndrome is a well-characterized genomic disorder caused by 4p16.3 deletions. Wolf-Hirschhorn syndrome patients exhibit characteristic facial dysmorphism, growth retardation, developmental delay, intellectual disability and seizure disorders. Recently, NSD2 gene located within the 165 kb Wolf-Hirschhorn syndrome critical region was identified as the key causal gene responsible for most if not all phenotypes of Wolf-Hirschhorn syndrome. So far, eight NSD2 loss of function variants have been reported in patients from different parts of the world, all were de novo variants. Methods In our study, we performed whole exome sequencing for two patients from one family. We also reviewed more NSD2 mutation cases in pervious literature. Results A novel loss of function NSD2 variant, c.1577dupG (p.Asn527Lysfs*14), was identified in a Chinese family in the proband and her father both affected with intellectual disability. After reviewing more NSD2 mutation cases in pervious literature, we found none of them had facial features that can be recognized as Wolf-Hirschhorn syndrome. In addition, we have given our proband growth hormone and followed up with this family for 7.5 years. Conclusions Here we reported the first familial NSD2 variant and the long-term effect of growth hormone therapy for patients. Our results suggested NSD2 mutation might cause a distinct intellectual disability and short stature syndrome.

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Clonazepam as an Effective Treatment for Epilepsy in a Female Patient with NEXMIF Mutation: Case Report

Molecular Syndromology ◽

10.1159/000510172 ◽

2020 ◽

Vol 11 (4) ◽

pp. 232-238 ◽

Cited By ~ 1

Author(s):

Masashi Ogasawara ◽

Eiji Nakagawa ◽

Eri Takeshita ◽

Kohei Hamanaka ◽

Satoko Miyatake ◽

...

Keyword(s):

Intellectual Disability ◽

Female Patient ◽

De Novo ◽

Intractable Epilepsy ◽

Good Choice ◽

De Novo Mutation ◽

Facial Dysmorphism ◽

Mild Intellectual Disability ◽

Female Patients ◽

Male Patients

The NEXMIF (KIAA2022) gene is located in the X chromosome, and hemizygous mutations in NEXMIF cause X-linked intellectual disability in male patients. Female patients with heterozygous mutations in NEXMIF also show similar, but milder, intellectual disability. Most female patients demonstrate intractable epilepsy compared with male patients, and the treatment strategy for epilepsy is still uncertain. Thus far, 24 female patients with NEXMIF mutations have been reported. Of these 24 patients, 20 also have epilepsy. Until now, epilepsy has been controlled in only 2 of these female patients. We report a female patient with a heterozygous de novo mutation, NM_001008537.2:c.1123del (p.Glu375Argfs*21), in NEXMIF. The patient showed mild intellectual disability, facial dysmorphism, obesity, generalized tonic-clonic seizures, and nonconvulsive status epilepticus. Sodium valproate was effective but caused secondary amenorrhea. We successfully treated her epilepsy with clonazepam without side effects, indicating that clonazepam might be a good choice to treat epilepsy in patients with NEXMIF mutations.

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IL1RAPL1 Gene Deletion in a Female Patient with Developmental Delay and Continuous Spike-Wave during Sleep

Journal of Pediatric Epilepsy ◽

10.1055/s-0041-1731816 ◽

2021 ◽

Author(s):

Evan Jiang ◽

Mark P. Fitzgerald ◽

Katherine L. Helbig ◽

Ethan M. Goldberg

Keyword(s):

Intellectual Disability ◽

Developmental Delay ◽

Synapse Formation ◽

De Novo ◽

Interleukin 1 ◽

Autism Spectrum ◽

Neurological Dysfunction ◽

Behavioral Disorder ◽

Clinical Genetic ◽

Severe Intellectual Disability

AbstractInterleukin-1 receptor accessory protein-like 1 (IL1RAPL1) encodes a protein that is highly expressed in neurons and has been shown to regulate neurite outgrowth as well as synapse formation and synaptic transmission. Clinically, mutations in or deletions of IL1RAPL1 have been associated with a spectrum of neurological dysfunction including autism spectrum disorder and nonsyndromic X-linked developmental delay/intellectual disability of varying severity. Nearly all reported cases are in males; in the few reported cases involving females, the clinical presentation was mild or the deletion was identified in phenotypically normal carriers in accordance with X-linked inheritance. Using genome-wide microarray analysis, we identified a novel de novo 373 kb interstitial deletion of the X chromosome (Xp21.1-p21.2) that includes exons 4 to 6 of the IL1RAPL1 gene in an 8-year-old girl with severe intellectual disability and behavioral disorder with a history of developmental regression. Overnight continuous video electroencephalography revealed electrical status epilepticus in sleep (ESES). This case expands the clinical genetic spectrum of IL1RAPL1-related neurodevelopmental disorders and highlights a new genetic association of ESES.

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A de novo variant in CASK gene causing intellectual disability and brain hypoplasia: A Case Report and Literature Review

10.21203/rs.3.rs-317232/v1 ◽

2021 ◽

Author(s):

Ying Zhang ◽

Yanyan Nie ◽

Yu Mu ◽

Jie Zheng ◽

Xiaowei Xu ◽

...

Keyword(s):

Intellectual Disability ◽

Mental Disorders ◽

De Novo ◽

Clinical Symptoms ◽

Clinical Manifestations ◽

De Novo Mutation ◽

Loss Of Function ◽

Bioinformatics Analyses ◽

Whole Exome ◽

De Novo Variant

Abstract Background：The pathogenic variation of CASK gene can cause CASK related mental disorders. The main clinical manifestations are microcephaly with pontine and cerebellar hypoplasia, X-linked mental disorders with or without nystagmus and FG syndrome. The main pathogenic mechanism is the loss of function of related protein caused by mutation. We reported a Chinese male newborn with a de novo variant in CASK gene. Case presentation：We present an 18-day-old baby with intellectual disability and brain hypoplasia. Whole-exome sequencing was performed, which detected a hemizygous missense mutation c.764G>A of CASK gene. The mutation changed the 255th amino acid from Arg to His. Software based bioinformatics analyses were conducted to infer its functional effect.Conclusions：In this paper, a de novo mutation of CASK gene was reported. Moreover, a detailed description of all the cases described in the literature is reported.CASK mutations cause a variety of clinical phenotypes. Its diagnosis is difficult due to the lack of typical clinical symptoms. Genetic testing should be performed as early as possible if this disease is suspected. This case provides an important reference for the diagnosis and treatment of future cases.

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MED13L-related intellectual disability due to paternal germinal mosaicism

Molecular Case Studies ◽

10.1101/mcs.a006124 ◽

2021 ◽

pp. mcs.a006124

Author(s):

Beata Bessenyei ◽

Istvan Balogh ◽

Attila Mokanszki ◽

Aniko Ujfalusi ◽

Rolph Pfundt ◽

...

Keyword(s):

Intellectual Disability ◽

De Novo ◽

Mediator Complex ◽

Facial Dysmorphism ◽

Facial Features ◽

Speech Delay ◽

Motor Delay ◽

First Case ◽

Intragenic Deletion ◽

Germinal Mosaicism

The MED13L-related intellectual disability or MRFACD syndrome (Mental retardation and distinctive facial features with or without cardiac defects; MIM # 616789) is one of the most common form of syndromic intellectual disability with about a hundred cases reported so far. Affected individuals share overlapping features comprising intellectual disability, hypotonia, motor delay, remarkable speech delay, and a recognizable facial gestalt. De novo disruption of the MED13L gene by deletions, duplications or sequence variants has been identified deleterious. Siblings affected by intragenic deletion transmitted from a mosaic parent have been reported once in the literature. We now present the first case of paternal germinal mosaicism for a missense MED13L variant causing MRFACD syndrome in one of the father's children and be the likely cause of intellectual disability and facial dysmorphism in the other. As part of the Mediator complex, the MED proteins have an essential role in regulating transcription. 32 subunits of the Mediator complex genes have been linked to congenital malformations that are now acknowledged as transcriptomopathies. The MRFACD syndrome has been suggested to represent a recognizable phenotype.

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Acute pre-B lymphoblastic leukemia and congenital anomalies in a child with a de novo 22q11.1q11.22 duplication

Balkan Journal of Medical Genetics ◽

10.2478/bjmg-2018-0002 ◽

2018 ◽

Vol 21 (1) ◽

pp. 87-91 ◽

Cited By ~ 1

Author(s):

M Vaisvilas ◽

V Dirse ◽

B Aleksiuniene ◽

I Tamuliene ◽

L Cimbalistiene ◽

...

Keyword(s):

Congenital Heart ◽

De Novo ◽

Heart Defects ◽

Lymphoblastic Leukemia ◽

Snp Array ◽

Facial Dysmorphism ◽

Severe Intellectual Disability ◽

Leukemic Clone ◽

Cell Growth And Differentiation ◽

Facial Dysmorphia

Abstract Microdeletions and microduplications are recurrent in the q11.2 region of chromosome 22. The 22q11.2 duplication syndrome is an extremely variable disorder with a phenotype ranging from severe intellectual disability, facial dysmorphism, heart defects, and urogenital abnormalities to very mild symptoms. Both benign and malignant hematological entities are rare. A male patient was diagnosed with mild facial dysmorphia, congenital heart anomalies shortly after birth and acute bowel obstruction due to malrotation of the intestine at the age of 3 years. A whole-genome single nucleotide polymorphism (SNP) array revealed a de novo 6.6 Mb duplication in the 22q11.1q11.22 chromosomal region. A year later, the patient was diagnosed with acute pre-B lymphoblastic leukemia (pre-B ALL). Five genes, CDC45, CLTCL1, DGCR2, GP1BB and SEPT5, in the 22q11.1q11.22 region are potentially responsible for cell cycle division. We hypothesized that dosage imbalance of genes implicated in the rearrangement could have disrupted the balance between cell growth and differentiation and played a role in the initiation of malignancy with a hyperdiploid leukemic clone, whereas over-expression of the TBX1 gene might have been responsible for congenital heart defects and mild facial dysmorphia.

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Pathogenic WDFY3 variants cause neurodevelopmental disorders and opposing effects on brain size

Brain ◽

10.1093/brain/awz198 ◽

2019 ◽

Vol 142 (9) ◽

pp. 2617-2630 ◽

Cited By ~ 6

Author(s):

Diana Le Duc ◽

Cecilia Giulivi ◽

Susan M Hiatt ◽

Eleonora Napoli ◽

Alexios Panoutsopoulos ◽

...

Keyword(s):

Intellectual Disability ◽

Wnt Pathway ◽

De Novo ◽

Autism Spectrum ◽

Neural Progenitors ◽

Scaffolding Protein ◽

Published Data ◽

Ph Domain ◽

Human Phenotype ◽

Neurodevelopmental Delay

Abstract The underpinnings of mild to moderate neurodevelopmental delay remain elusive, often leading to late diagnosis and interventions. Here, we present data on exome and genome sequencing as well as array analysis of 13 individuals that point to pathogenic, heterozygous, mostly de novo variants in WDFY3 (significant de novo enrichment P = 0.003) as a monogenic cause of mild and non-specific neurodevelopmental delay. Nine variants were protein-truncating and four missense. Overlapping symptoms included neurodevelopmental delay, intellectual disability, macrocephaly, and psychiatric disorders (autism spectrum disorders/attention deficit hyperactivity disorder). One proband presented with an opposing phenotype of microcephaly and the only missense-variant located in the PH-domain of WDFY3. Findings of this case are supported by previously published data, demonstrating that pathogenic PH-domain variants can lead to microcephaly via canonical Wnt-pathway upregulation. In a separate study, we reported that the autophagy scaffolding protein WDFY3 is required for cerebral cortical size regulation in mice, by controlling proper division of neural progenitors. Here, we show that proliferating cortical neural progenitors of human embryonic brains highly express WDFY3, further supporting a role for this molecule in the regulation of prenatal neurogenesis. We present data on Wnt-pathway dysregulation in Wdfy3-haploinsufficient mice, which display macrocephaly and deficits in motor coordination and associative learning, recapitulating the human phenotype. Consequently, we propose that in humans WDFY3 loss-of-function variants lead to macrocephaly via downregulation of the Wnt pathway. In summary, we present WDFY3 as a novel gene linked to mild to moderate neurodevelopmental delay and intellectual disability and conclude that variants putatively causing haploinsufficiency lead to macrocephaly, while an opposing pathomechanism due to variants in the PH-domain of WDFY3 leads to microcephaly.

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A Novel SETBP1 Gene Disruption by a De Novo Balanced Translocation in a Patient with Speech Impairment, Intellectual, and Behavioral Disorder

Journal of Pediatric Genetics ◽

10.1055/s-0040-1715639 ◽

2020 ◽

Author(s):

Ivona Vrkić Boban ◽

Futoshi Sekiguchi ◽

Mirela Lozić ◽

Noriko Miyake ◽

Naomichi Matsumoto ◽

...

Keyword(s):

Intellectual Disability ◽

Autosomal Dominant ◽

De Novo ◽

Chromosomal Abnormalities ◽

Chromosome Translocation ◽

Behavioral Disorder ◽

Behavioral Difficulties ◽

Speech Impairment ◽

Balanced Translocation ◽

Severe Intellectual Disability

AbstractBalanced chromosomal abnormalities (BCAs) can disrupt gene function resulting in disease. To date, BCA disrupting the SET binding protein 1 (SETBP1) gene has not been reported. On the other hand, de novo heterozygous variants in the highly conserved 11-bp region in SETBP1 can result in the Schinzel–Giedion syndrome. This condition is characterized by severe intellectual disability, a characteristic face, and multiple-system anomalies. Further other types of mutations involving SETBP1 are associated with a different phenotype, mental retardation, autosomal dominant 29 (MRD29), which has mild dysmorphic features, developmental delay, and behavioral disorders. Here we report a male patient who has moderate intellectual disability, mild behavioral difficulties, and severe expressive speech impairment resulting from a de novo balanced chromosome translocation, t(12;18)(q22;q12.3). By whole genome sequencing, we determined the breakpoints at the nucleotide level. The 18q12.3 breakpoint was located between exons 2 and 3 of SETBP1. Phenotypic features of our patient are compatible with those with MRD29. This is the first reported BCA disrupting SETBP1.

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