OTUD5 Variants Associated With X-Linked Intellectual Disability and Congenital Malformation

BackgroundX-linked intellectual disability (XLID), which occurs predominantly in males, is a relatively common and genetically heterogeneous disorder in which over 100 mutated genes have been reported. The OTUD5 gene at Xp11.23 encodes ovarian tumor deubiquitinase 5 protein, which is a deubiquitinating enzyme member of the ovarian tumor family. LINKage-specific-deubiquitylation-deficiency-induced embryonic defects (LINKED) syndrome, arising from pathogenic OTUD5 variants, was recently reported as a new XLID with additional congenital anomalies.MethodsWe investigated three affected males (49- and 47-year-old brothers [Individuals 1 and 2] and a 2-year-old boy [Individual 3]) from two families who showed developmental delay. Their common clinical features included developmental delay, hypotonia, short stature, and distinctive facial features, such as telecanthus and a depressed nasal bridge. Individuals 1 and 2 showed epilepsy and brain magnetic resonance imaging showed a thin corpus callosum and mild ventriculomegaly. Individual 3 showed congenital malformations, including tetralogy of Fallot, hypospadias, and bilateral cryptorchidism. To identify the genetic cause of these features, we performed whole-exome sequencing.ResultsA hemizygous OTUD5 missense variant, c.878A>T, p.Asn293Ile [NM_017602.4], was identified in one family with Individuals 1 and 2, and another missense variant, c.1210 C>T, p.Arg404Trp, in the other family with Individual 3, respectively. The former variant has not been registered in public databases and was predicted to be pathogenic by multiple in silico prediction tools. The latter variant p.Arg404Trp was previously reported as a pathogenic OTUD5 variant, and Individual 3 showed a typical LINKED syndrome phenotype. However, Individuals 1 and 2, with the novel variant (p.Asn293Ile), showed no cardiac or genitourinary malformations.ConclusionsUnlike previous reports of LINKED syndrome, which described early lethality with congenital cardiac anomalies, our three cases are still alive. Notably, the adult brothers with the novel missense OTUD5 variant have lived into their forties. This may be indicative of a milder phenotype as a possible genotype-phenotype correlation. These findings imply a possible long-term prognosis for individuals with this new XLID syndrome, and a wider phenotypic variation than initially thought.

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Shukla-Vernon Syndrome: A Second Family with a Novel Variant in the BCORL1 Gene

Genes ◽

10.3390/genes12030452 ◽

2021 ◽

Vol 12 (3) ◽

pp. 452

Author(s):

Babylakshmi Muthusamy ◽

Anikha Bellad ◽

Satish Chandra Girimaji ◽

Akhilesh Pandey

Keyword(s):

Intellectual Disability ◽

Developmental Delay ◽

Protein Complexes ◽

Neurodevelopmental Disorder ◽

Missense Variant ◽

Global Developmental Delay ◽

Dysmorphic Features ◽

Pathogenic Variants ◽

Behavioral Abnormalities ◽

Novel Variant

Shukla-Vernon syndrome (SHUVER) is an extremely rare neurodevelopmental disorder characterized by global developmental delay, intellectual disability, behavioral anomalies, and dysmorphic features. Pathogenic variants in the BCORL1 gene have been identified as the molecular cause for this disorder. The BCORL1 gene encodes for BCL-6 corepressor-like protein 1, a transcriptional corepressor that is an integral component of protein complexes involved in transcription repression. In this study, we report an Indian family with two male siblings with features of Shukla-Vernon syndrome. The patients exhibited global developmental delay, intellectual disability, kyphosis, seizures, and dysmorphic features including bushy prominent eyebrows with synophrys, sharp beaked prominent nose, protuberant lower jaw, squint, and hypoplastic ears with fused ear lobes. No behavioral abnormalities were observed. Whole exome sequencing revealed a novel potentially pathogenic arginine to cysteine substitution (p.Arg1265Cys) in the BCORL1 protein. This is the second report of Shukla-Vernon syndrome with a novel missense variant in the BCORL1 gene. Our study confirms and expands the phenotypes and genotypes described previously for this syndrome and should aid in diagnosis and genetic counselling of patients and their families.

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Novel compound heterozygous mutations in WDR62 gene leading to developmental delay and Primary Microcephaly in Saudi Family

Pakistan Journal of Medical Sciences ◽

10.12669/pjms.35.3.36 ◽

2019 ◽

Vol 35 (3) ◽

Author(s):

Muhammad Imran Naseer ◽

Mahmood Rasool ◽

Angham Abdulrahman Abdulkareem ◽

Adeel G. Chaudhary ◽

Syed Kashif Zaidi ◽

...

Keyword(s):

Intellectual Disability ◽

Developmental Delay ◽

Genetic Defect ◽

Compound Heterozygous ◽

Sequencing Analysis ◽

The Novel ◽

Primary Microcephaly ◽

Saudi Family ◽

Exon 9 ◽

Compound Heterozygous Mutations

Objective: Primary microcephaly (MCPH) is a rare autosomal recessive disorder characterized by impaired congenital reduction of brain size along with head circumference and intellectual disability. MCPH is a heterogeneous disorder and more than twenty four genes associated with this disease have been identified so far. The objective of this study was to find out the novel genes or mutations leading to the genetic defect in a Saudi family with primary microcephaly. Methods: Whole exome sequencing was carried out to find the novel mutation and the results was further validated using Sanger sequencing analysis. This study was done in the Center of excellence in Genomic Medicine and Research, King Abdulaziz University under KACST project during 2017 and 2018. Results: We report a novel compound heterozygous mutations c.797C>T in exon 7 and c.1102G>A in exon 9 of the WD repeat domain 62 (WDR62) (OMIM 604317) gene in two affected siblings in Saudi family with intellectual disability, speech impediments walking difficulty along with primary microcephaly. Two rare, missense variants were detected in heterozygous state in the WDR62 gene in these two affected individuals from the heterozygous parents. Conclusions: A compound heterozygous mutations c.797C>T in exon 7 and c.1102G> A in exon 9 of the WDR62 gene was identified. WDR62 gene is very important gene and mutation can lead to neuro developmental defects, brain malformations, reduced brain and head size. These results should be taken into consideration during prognostic discussions and mutation spectrum with affected patients and their families in the Saudi population. doi: https://doi.org/10.12669/pjms.35.3.36 How to cite this:Naseer MI, Rasool M, Abdulkareem AA, Chaudhary AG, Zaidi SK, Al-Qahtani MH. Novel compound heterozygous mutations in WDR62 gene leading to developmental delay and Primary Microcephaly in Saudi Family. Pak J Med Sci. 2019;35(3):---------. doi: https://doi.org/10.12669/pjms.35.3.36 This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

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Novel Imaging and Clinical Manifestations of Ndmsba Disorder Caused by a Homozygous Missense Variant of Plaa

10.21203/rs.3.rs-407675/v1 ◽

2021 ◽

Author(s):

Ali Dehghani ◽

Ehsan Razmara ◽

Maryam Rasoulinezhad ◽

Fatemeh Bitarafan ◽

Ali Reza Tavasoli ◽

...

Keyword(s):

White Matter ◽

Neurodevelopmental Disorder ◽

Clinical Manifestations ◽

Brain Magnetic Resonance Imaging ◽

Missense Variant ◽

The Novel ◽

Neurodevelopmental Disease ◽

Brain Anomalies ◽

Whole Exome ◽

Magnetic Resonance Imaging Mri

Abstract BackgroundPhospholipase A-2-activating protein (PLAP) has essential roles in biological pathways. Neurodevelopmental disorder with progressive microcephaly, spasticity, and brain anomalies (NDMSBA) is a complex neurodevelopmental disease caused by defects in the PLAA gene (MIM: 603873). Herein, we aimed to detect the potential genetic factors contributing to the NDMSBA phenotype in a 2.5-year-old affected male in an Iranian consanguineous family.ResultsAfter meticulously performing neuroimaging and clinical examinations, due to heterogeneity of neurodevelopmental diseases, the proband was subjected to paired-end whole-exome sequencing (WES). The brain magnetic resonance imaging (MRI) revealed lissencephaly, polymicrogyria, severe subcortical, deep and deep white matter signal abnormalities, thinning of the corpus callosum, and severe vermis atrophy. Interestingly, we detected a novel homozygous missense variant, NM_001031689.3:c.2264A>G;p.(Asp755Gly) in the PLAA gene. To the best of our knowledge, this variant is the second one identified within the PUL domain (PLAP, Ufd3p, and Lub1p) of PLAP and also the sixth reported variant throughout the PLAA gene. In silico analyses underscored the pathogenicity of the variant. ConclusionsThe present study demonstrated severe cerebral and cerebellar white matter signal abnormalities, hypertelorism, strabismus, and drooling in the proband as the novel manifestation of NDMSBA that in turn caused by a novel likely pathogenic missense variant. Further studies are required to confirm how this variant contributes to NDMSBA.

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New Imaging and Clinical Manifestations of NDMSBA Disorder Caused by a Novel Homozygous Missense Variant of PLAA

10.21203/rs.3.rs-464604/v1 ◽

2021 ◽

Author(s):

Ali Dehghani ◽

Ehsan Razmara ◽

Maryam Rasoulinezhad ◽

Fatemeh Bitarafan ◽

Ali Reza Tavasoli ◽

...

Keyword(s):

White Matter ◽

In Silico ◽

Neurodevelopmental Disorder ◽

Clinical Manifestations ◽

Brain Magnetic Resonance Imaging ◽

Missense Variant ◽

The Novel ◽

Neurodevelopmental Disease ◽

Brain Anomalies ◽

Whole Exome

Abstract Background: Phospholipase A-2-activating protein (PLAP) has essential roles in biological pathways. Neurodevelopmental disorder with progressive microcephaly, spasticity, and brain anomalies (NDMSBA) is a complex neurodevelopmental disease caused by defects in the PLAA gene (MIM: 603873). Herein, we aimed to detect the potential genetic factors contributing to the NDMSBA phenotype in a 2.5-year-old affected male in an Iranian consanguineous family.Methods: After meticulously performing neuroimaging and clinical examinations, due to heterogeneity of neurodevelopmental diseases, the proband was subjected to paired-end whole-exome sequencing (WES). The candidate variant was confirmed by Sanger sequencing and different in silico predictions were used to show the pathogenicity of the variant. Results: The brain magnetic resonance imaging revealed lissencephaly, polymicrogyria, severe subcortical, deep and deep white matter signal abnormalities, thinning of the corpus callosum, and severe vermis atrophy. Interestingly, we detected a novel homozygous missense variant, NM_001031689.3:c.2264A>G;p.(Asp755Gly) in the PLAA gene. To the best of our knowledge, this variant is the second one identified within the PUL domain (PLAP, Ufd3p, and Lub1p) of PLAP and also the sixth reported variant throughout the PLAA gene. In silico analyses underscored the pathogenicity of the variant. Conclusions: The present study demonstrated severe cerebral and cerebellar white matter signal abnormalities, hypertelorism, strabismus, and drooling in the proband as the novel manifestation of NDMSBA that in turn caused by a novel likely pathogenic missense variant. Further studies are required to confirm how this variant contributes to NDMSBA.

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A novel de novo KDM5C variant in a female with global developmental delay and ataxia: a case report

BMC Neurology ◽

10.1186/s12883-021-02380-9 ◽

2021 ◽

Vol 21 (1) ◽

Author(s):

Natalie C. Lippa ◽

Subit Barua ◽

Vimla Aggarwal ◽

Elaine Pereira ◽

Jennifer M. Bain

Keyword(s):

Case Report ◽

Intellectual Disability ◽

Short Stature ◽

Developmental Delay ◽

De Novo ◽

Phenotypic Variability ◽

Missense Variant ◽

Global Developmental Delay ◽

Related Disorder ◽

Patient Reported

Abstract Background Pathogenic variants in KDM5C are a cause of X-linked intellectual disability in males. Other features in males include short stature, dysmorphic features, seizures and spasticity. In some instances, female relatives were noted to have learning difficulties and mild intellectual disabilities, but full phenotypic descriptions were often incomplete. Recently, detailed phenotypic features of five affected females with de novo variants were described. (Clin Genet 98:43–55, 2020) Four individuals had a protein truncating variant and 1 individual had a missense variant. All five individuals had developmental delay/intellectual disability and three neurological features. Case presentation Here we report a three-year-old female with global developmental delay, hypotonia and ataxia. Through whole exome sequencing, a de novo c.1516A > G (p.Met506Val) variant in KDM5C was identified. This missense variant is in the jumonji-C domain of this multi domain protein where other missense variants have been previously reported in KDM5C related disorder. The KDM5C gene is highly intolerant to functional variation which suggests its pathogenicity. The probands motor delays and language impairment is consistent with other reported female patients with de novo variants in KDM5C. However, other features reported in females (distinctive facial features, skeletal abnormalities, short stature and endocrine features) were absent. To the best of our knowledge, our proband is the first female patient reported with a diagnosis of ataxia. Conclusions This case report provides evidence for an emerging and phenotypic variability that adds to the literature of the role of KDM5C in females with neurodevelopmental disorders as well as movement disorders.

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Novel CLCN4 variant associated with syndromic X-linked intellectual disability in a Chinese girl: a case report

BMC Pediatrics ◽

10.1186/s12887-021-02860-4 ◽

2021 ◽

Vol 21 (1) ◽

Author(s):

Xin Xu ◽

Fen Lu ◽

Li Zhang ◽

Hongying Li ◽

Senjie Du ◽

...

Keyword(s):

Intellectual Disability ◽

Language Impairment ◽

Brain Magnetic Resonance Imaging ◽

Rare Condition ◽

Missense Variant ◽

Brain Abnormalities ◽

Case Presentation ◽

Whole Exome ◽

Chinese Girl ◽

Magnetic Resonance Imaging Mri

Abstract Background The Raynaud-Claes type of X-linked syndromic mental retardation (MRXSRC) is a very rare condition, by intellectual disability ranged from borderline to profound, impaired language development, brain abnormalities, facial dysmorphisms and seizures. MRXSRC is caused by variants in CLCN4 which encodes the 2Cl−/H+ exchanger ClC-4 prominently expressed in brain. Case presentation We present a 3-year-old Chinese girl with intellectual disability, dysmorphic features, brain abnormalities, significant language impairment and autistic features. Brain magnetic resonance imaging (MRI) showed a thin corpus callosum, a mega cisterna magna and ventriculomegaly. Whole exome sequencing (WES) was performed to detect the molecular basis of the disease. It was confirmed that this girl carried a novel heterozygous missense variant (c.1343C > T, p.Ala448Val) of CLCN4 gene, inherited from her mother. This variant has not been registered in public databases and was predicted to be pathogenic by multiple in silico prediction tools. Conclusion Our investigation expands the phenotype spectrum for CLCN4 variants with syndromic X-linked intellectual disability, which help to improve the understanding of CLCN4-related intellectual disability and will help in genetic counselling for this family.

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Identifying Clinical Clues in Children With Global Developmental Delay / Intellectual Disability With Abnormal Brain Magnetic Resonance Imaging (MRI)

Journal of Child Neurology ◽

10.1177/0883073820977330 ◽

2020 ◽

pp. 088307382097733

Author(s):

Abdullah Alamri ◽

Yaser I. Aljadhai ◽

Abdullah Alrashed ◽

Bandar Alfheed ◽

Roba Abdelmoaty ◽

...

Keyword(s):

Magnetic Resonance Imaging ◽

Intellectual Disability ◽

Magnetic Resonance ◽

Developmental Delay ◽

Brain Mri ◽

Brain Magnetic Resonance Imaging ◽

Global Developmental Delay ◽

Resonance Imaging ◽

Mri Findings ◽

Magnetic Resonance Imaging Mri

Global developmental delay / intellectual disability are common pediatric conditions. Brain magnetic resonance imaging (MRI), although an important diagnostic tool in the evaluation of these patients, often requires general anesthesia. Recent literature suggests that unnecessary general anesthesia exposure should be avoided in early years because of possible long-term negative neurodevelopmental sequelae. This study sought to identify clinical clues associated with brain MRI abnormalities in children with global developmental delay / intellectual disability in an attempt to provide guidance to physicians on selecting patients who would benefit from an MRI. Retrospective chart review analysis was conducted for patients presenting to a pediatric neurology tertiary care center between 2014 and 2017 for a first clinic evaluation for global developmental delay / intellectual disability. Detailed clinical history and physical examination findings were analyzed and correlated with brain MRI findings. The majority (218/327, 67%) of children referred for evaluation of global developmental delay / intellectual disability underwent complete clinical and radiologic evaluations. Mean age was 37.9 months (±32.5 standard deviation) and 116 were males (53%). Motor deficits were predominant in most subjects (122/218, 56%). Abnormal MRI findings were observed in 153 children (70%), with the most prevalent abnormalities noted within the white matter (104/153, 68%), corpus callosum (77/153, 50%), and the hippocampus (50/153, 33%). Abnormal MRI findings were prevalent in children with predominant motor delay (84, 69%) and cognitive disability (3, 100%) as well as those with visual and hearing impairment ( P < .05). The presence of facial dysmorphisms (57/71, P = .02); cranial nerve abnormalities (79/100; P = .007) and abnormal reflexes (16, P = .01) on examination also correlated significantly with increased MRI abnormalities.

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Effectiveness of Chloral Hydrate on Brain MRI in Children with Developmental Delay/Intellectual Disability Comparing with Normal Intelligence: Single Tertiary Center Experience

Children ◽

10.3390/children8121097 ◽

2021 ◽

Vol 8 (12) ◽

pp. 1097

Author(s):

Ja Un Moon ◽

Ji Yoon Han

Keyword(s):

Intellectual Disability ◽

Developmental Delay ◽

Chloral Hydrate ◽

Adverse Reactions ◽

Brain Mri ◽

Brain Magnetic Resonance Imaging ◽

Vulnerable Groups ◽

Sedative Drug ◽

Normal Intelligence ◽

Tertiary Center

Neurodiagnostic investigation requirements are expanding for diagnostic and therapeutic purposes in children, especially in those with developmental delay/intellectual disability (DD/ID). Thus, determination of optimal sedatives to achieve successful sedation and immobility without further neurological compromise is important in children with DD/ID. The purpose of this study is to assess the effectiveness and adverse reactions of chloral hydrate (CH) for brain magnetic resonance imaging (B-MRI) in children with DD/ID compared to those with normal intelligence (NI). We performed a retrospective chart review of children aged from 1 day to 12 years who required elective sedation using CH for B-MRI. About 730 cases (415 with DD/ID and 315 with NI) of CH sedation were conducted for B-MRI. Children with DD/ID showed a higher failure rate (22%) than did those with NI (6%); additional CH and prolonged sedation time were required. There was no difference in incidence of adverse reactions between DD/ID and NI groups (p = 0.338). Older or heavier children with DD/ID (p = 0.036 and p = 0.013, respectively), as well as those diagnosed with epilepsy or neuropsychiatric disorders showed higher risk of sedation failure (p < 0.001 for each). In conclusion, CH was a suboptimal sedative drug for children with DD/ID compared with those with NI. Other alternative or supplementary sedatives should be taken into consideration especially for those vulnerable groups.

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