Pathogenic variants in PIDD1 lead to an autosomal recessive neurodevelopmental disorder with pachygyria and psychiatric features

AbstractThe PIDDosome is a multiprotein complex, composed by the p53-induced death domain protein 1 (PIDD1), the bipartite linker protein CRADD (also known as RAIDD) and the proform of caspase-2 that induces apoptosis in response to DNA damage. In the recent years, biallelic pathogenic variants in CRADD have been associated with a neurodevelopmental disorder (MRT34; MIM 614499) characterized by pachygyria with a predominant anterior gradient, megalencephaly, epilepsy and intellectual disability. More recently, biallelic pathogenic variants in PIDD1 have been described in a few families with apparently nonsydnromic intellectual disability. Here, we aim to delineate the genetic and radio-clinical features of PIDD1-related disorder. Exome sequencing was carried out in six consanguineous families. Thorough clinical and neuroradiological evaluation was performed for all the affected individuals as well as reviewing all the data from previously reported cases. We identified five distinct novel homozygous variants (c.2584C>T p.(Arg862Trp), c.1340G>A p.(Trp447*), c.2116_2120del p.(Val706Hisfs*30), c.1564_1565delCA p.(Gln522fs*44), and c.1804_1805del p.(Gly602fs*26) in eleven subjects displaying intellectual disability, behaviorial and psychiatric features, and a typical anterior-predominant pachygyria, remarkably resembling the CRADD-related neuroimaging pattern. In summary, we outline the phenotypic and molecular spectrum of PIDD1 biallelic variants supporting the evidence that the PIDD1/CRADD/caspase-2 signaling is crucial for normal gyration of the developing human neocortex as well as cognition and behavior.

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Clinical characteristics of Polish patients with molecularly confirmed Mowat-Wilson syndrome

Journal of Applied Genetics ◽

10.1007/s13353-021-00636-1 ◽

2021 ◽

Author(s):

Aleksandra Jakubiak ◽

Krzysztof Szczałuba ◽

Magdalena Badura-Stronka ◽

Anna Kutkowska-Kaźmierczak ◽

Anna Jakubiuk-Tomaszuk ◽

...

Keyword(s):

Intellectual Disability ◽

Congenital Anomalies ◽

Chromosomal Region ◽

Neurodevelopmental Disorder ◽

Hirschsprung Disease ◽

Psychomotor Retardation ◽

Facial Features ◽

Dysmorphic Features ◽

Pathogenic Variants ◽

Intragenic Deletions

AbstractMowat-Wilson syndrome is a rare neurodevelopmental disorder caused by pathogenic variants in the ZEB2 gene, intragenic deletions of the ZEB2 gene, and microdeletions in the critical chromosomal region 2q22-23, where the ZEB2 gene is located. Mowat-Wilson syndrome is characterized by typical facial features that change with the age, severe developmental delay with intellectual disability, and multiple congenital abnormalities. The authors describe the clinical and genetic aspects of 28th patients with Mowat-Wilson syndrome diagnosed in Poland. Characteristic dysmorphic features, psychomotor retardation, intellectual disability, and congenital anomalies were present in all cases. The incidence of most common congenital anomalies (heart defect, Hirschsprung disease, brain defects) was similar to presented in literature. Epilepsy was less common compared to previously reported cases. Although the spectrum of disorders in patients with Mowat-Wilson syndrome is wide, knowledge of characteristic dysmorphic features awareness of accompanying abnormalities, especially intellectual disability, improves detection of the syndrome.

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Identification of candidate gene FAM183A and novel pathogenic variants in known genes: High genetic heterogeneity for autosomal recessive intellectual disability

PLoS ONE ◽

10.1371/journal.pone.0208324 ◽

2018 ◽

Vol 13 (11) ◽

pp. e0208324 ◽

Cited By ~ 5

Author(s):

Megan McSherry ◽

Katherine E. Masih ◽

Nursel H. Elcioglu ◽

Pelin Celik ◽

Ozge Balci ◽

...

Keyword(s):

Intellectual Disability ◽

Candidate Gene ◽

Genetic Heterogeneity ◽

Autosomal Recessive ◽

Pathogenic Variants

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Biallelic truncation variants in ATP9A are associated with a novel autosomal recessive neurodevelopmental disorder

10.1101/2021.05.31.21257832 ◽

2021 ◽

Author(s):

Francesca Mattioli ◽

Hossein Darvish ◽

Sohail Aziz Paracha ◽

Abbas Tafakhori ◽

Saghar Ghasemi Firouzabadi ◽

...

Keyword(s):

Intellectual Disability ◽

Mouse Model ◽

Autosomal Recessive ◽

High Throughput Sequencing ◽

Neurodevelopmental Disorder ◽

Behavioral Changes ◽

Causative Role ◽

Speech Impairment ◽

Lipid Flippase

Intellectual disability (ID) is a highly heterogeneous disorder with hundreds of associated genes. Despite progress in the identification of the genetic causes of ID following the introduction of high-throughput sequencing, about half of affected individuals still remain without a molecular diagnosis. Consanguineous families with affected individuals provide a unique opportunity to identify novel recessive causative genes. In this report we describe a novel autosomal recessive neurodevelopmental disorder. We identified two consanguineous families with homozygous variants predicted to alter the splicing of ATP9A which encodes a transmembrane lipid flippase of the class II P4-ATPases. The three individuals homozygous for these putatively truncating variants presented with severe ID, motor and speech impairment, and behavioral anomalies. Consistent with a causative role of ATP9A in these patients, a previously described Atp9a-/- mouse model showed behavioral changes.

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Biallelic variants in PSMB1 encoding the proteasome subunit β6 cause impairment of proteasome function, microcephaly, intellectual disability, developmental delay and short stature

Human Molecular Genetics ◽

10.1093/hmg/ddaa032 ◽

2020 ◽

Vol 29 (7) ◽

pp. 1132-1143 ◽

Cited By ~ 2

Author(s):

Muhammad Ansar ◽

Frédéric Ebstein ◽

Hayriye Özkoç ◽

Sohail A Paracha ◽

Justyna Iwaszkiewicz ◽

...

Keyword(s):

Intellectual Disability ◽

Developmental Delay ◽

Autosomal Recessive ◽

Brain Size ◽

Autosomal Recessive Disorders ◽

Proteasome Subunit ◽

Pathogenic Variants ◽

The Family ◽

Proteasome Subunits ◽

Recessive Disorders

Abstract The molecular cause of the majority of rare autosomal recessive disorders remains unknown. Consanguinity due to extensive homozygosity unravels many recessive phenotypes and facilitates the detection of novel gene-disease links. Here, we report two siblings with phenotypic signs, including intellectual disability (ID), developmental delay and microcephaly from a Pakistani consanguineous family in which we have identified homozygosity for p(Tyr103His) in the PSMB1 gene (Genbank NM_002793) that segregated with the disease phenotype. PSMB1 encodes a β-type proteasome subunit (i.e. β6). Modeling of the p(Tyr103His) variant indicates that this variant weakens the interactions between PSMB1/β6 and PSMA5/α5 proteasome subunits and thus destabilizes the 20S proteasome complex. Biochemical experiments in human SHSY5Y cells revealed that the p(Tyr103His) variant affects both the processing of PSMB1/β6 and its incorporation into proteasome, thus impairing proteasome activity. CRISPR/Cas9 mutagenesis or morpholino knock-down of the single psmb1 zebrafish orthologue resulted in microcephaly, microphthalmia and reduced brain size. Genetic evidence in the family and functional experiments in human cells and zebrafish indicates that PSMB1/β6 pathogenic variants are the cause of a recessive disease with ID, microcephaly and developmental delay due to abnormal proteasome assembly.

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ST3GAL5-Related Disorders: A Deficiency in Ganglioside Metabolism and a Genetic Cause of Intellectual Disability and Choreoathetosis

Journal of Child Neurology ◽

10.1177/0883073818791099 ◽

2018 ◽

Vol 33 (13) ◽

pp. 825-831 ◽

Cited By ~ 3

Author(s):

Eliza Gordon-Lipkin ◽

Julie S. Cohen ◽

Siddharth Srivastava ◽

Bruno P. Soares ◽

Eric Levey ◽

...

Keyword(s):

Intellectual Disability ◽

Neurodevelopmental Disorder ◽

Failure To Thrive ◽

Ganglioside Gm3 ◽

Normal Birth ◽

Pathogenic Variants ◽

Gm3 Synthase ◽

Whole Exome ◽

Ganglioside Metabolism ◽

Autosomal Recessive Condition

GM3 synthase deficiency is due to biallelic pathogenic variants in ST3GAL5, which encodes a sialyltransferase that synthesizes ganglioside GM3. Key features of this rare autosomal recessive condition include profound intellectual disability, failure to thrive and infantile onset epilepsy. We expand the phenotypic spectrum with 3 siblings who were found by whole exome sequencing to have a homozygous pathogenic variant in ST3GAL5, and we compare these cases to those previously described in the literature. The siblings had normal birth history, subsequent developmental stagnation, profound intellectual disability, choreoathetosis, failure to thrive, and visual and hearing impairment. Ichthyosis and self-injurious behavior are newly described in our patients and may influence clinical management. We conclude that GM3 synthase deficiency is a neurodevelopmental disorder with consistent features of profound intellectual disability, choreoathetosis, and deafness. Other phenotypic features have variable expressivity, including failure to thrive, epilepsy, regression, vision impairment, and skin findings. Our analysis demonstrates a broader phenotypic range of this potentially under-recognized disorder.

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Autosomal Recessive Primary Microcephaly (MCPH): An Update

Neuropediatrics ◽

10.1055/s-0037-1601448 ◽

2017 ◽

Vol 48 (03) ◽

pp. 135-142 ◽

Cited By ~ 21

Author(s):

Deborah Morris-Rosendahl ◽

Angela Kaindl ◽

Sami Zaqout

Keyword(s):

Intellectual Disability ◽

Head Circumference ◽

Autosomal Recessive ◽

Neurodevelopmental Disorder ◽

Speech Disorder ◽

Rare Disorder ◽

Primary Microcephaly ◽

Expressive Speech ◽

Autosomal Recessive Primary Microcephaly

AbstractAutosomal recessive primary microcephaly (MCPH; MicroCephaly Primary Hereditary) is a genetically heterogeneous neurodevelopmental disorder characterized by a significantly reduced head circumference present already at birth and intellectual disability. Inconsistent features include hyperactivity, an expressive speech disorder, and epilepsy. Here, we provide a brief overview on this rare disorder pertinent for clinicians.

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Novel variants identified in CKAP2L in two siblings with Filippi Syndrome

Molecular Case Studies ◽

10.1101/mcs.a006130 ◽

2021 ◽

pp. mcs.a006130

Author(s):

Ryan J Patrick ◽

Jill M Weimer ◽

Laura Davis-Keppen ◽

Megan L Landsverk

Keyword(s):

Intellectual Disability ◽

Autosomal Recessive ◽

Missense Variant ◽

Facial Features ◽

Loss Of Function ◽

Pathogenic Variants ◽

Whole Exome ◽

The Family ◽

Novel Variants ◽

In Trans

Pathogenic variants in CKAP2L have previously been reported in Filippi Syndrome (FS), a rare autosomal recessive, craniodigital syndrome characterized by microcephaly, syndactyly, short stature, intellectual disability, and dysmorphic facial features. To date, fewer than ten patients with pathogenic variants in CKAP2L associated with FS have been reported. All of the previously reported probands have presumed loss-of-function variants (frameshift, canonical splice site, starting methionine) and all but one have been homozygous for a pathogenic variant. Here we describe two brothers who presented with microcephaly, micrognathia, syndactyly, dysmorphic features, and intellectual disability. Whole exome sequencing of the family identified a missense variant, c.2066G>A (p.Arg689His), in trans with a frameshift variant, c.1169_1173del (p.Ile390LysfsTer4), in CKAP2L. To our knowledge, these are the first patients with FS to be reported with a missense variant in CKAP2L and only the second family to be reported with two variants in trans.

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SLC12A2 mutations cause NKCC1 deficiency with encephalopathy and impaired secretory epithelia

Neurology Genetics ◽

10.1212/nxg.0000000000000478 ◽

2020 ◽

Vol 6 (4) ◽

pp. e478 ◽

Cited By ~ 3

Author(s):

Tommy Stödberg ◽

Måns Magnusson ◽

Nicole Lesko ◽

Anna Wredenberg ◽

Daniel Martin Munoz ◽

...

Keyword(s):

Autosomal Recessive ◽

Neurodevelopmental Disorder ◽

Brain Mri ◽

Autosomal Recessive Inheritance ◽

Recessive Inheritance ◽

Inheritance Pattern ◽

Loss Of Function ◽

Pathogenic Variants ◽

Gastrointestinal Problems ◽

Life Threatening

ObjectiveTo describe the phenotype in 2 sisters with a rare constellation of neurologic symptoms and secretory impairments and to identify the etiology by the use of whole-genome sequencing (WGS).MethodsAfter an extensive workup failed to reveal the cause of disease, in a girl with a previously not reported phenotype, WGS of the proband, her diseased older sister, an older healthy brother, and their parents was performed, and potentially pathogenic variants were analyzed.ResultsThe proband and her older sister both presented with neonatal Staphylococcus aureus parotitis, apneas, disappearance of the Moro reflex, and hypotonia. The proband survived. Her brain MRI showed white matter and basal ganglia abnormalities, and CSF damage biomarkers were increased. At age 8 years, she exhibits a constellation of symptoms including severe neurodevelopmental disorder, hearing impairment, gastrointestinal problems, and a striking lack of tear fluid, saliva, and sweat. Her respiratory mucosa is dry with potentially life-threatening mucus plugging. Through WGS, 2 loss-of-function variants in SLC12A2 were identified that follow an autosomal recessive inheritance pattern.ConclusionsTaken together with a single previously reported case and the close resemblance to the phenotypes of corresponding mouse models, our study firmly establishes biallelic variants in SLC12A2 as causing human disease and adds data regarding the neurologic phenotype.

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Biallelic truncation variants in ATP9A are associated with a novel autosomal recessive neurodevelopmental disorder

npj Genomic Medicine ◽

10.1038/s41525-021-00255-z ◽

2021 ◽

Vol 6 (1) ◽

Author(s):

Francesca Mattioli ◽

Hossein Darvish ◽

Sohail Aziz Paracha ◽

Abbas Tafakhori ◽

Saghar Ghasemi Firouzabadi ◽

...

Keyword(s):

Intellectual Disability ◽

Mouse Model ◽

Autosomal Recessive ◽

High Throughput Sequencing ◽

Neurodevelopmental Disorder ◽

Behavioral Changes ◽

Causative Role ◽

Speech Impairment ◽

Lipid Flippase

AbstractIntellectual disability (ID) is a highly heterogeneous disorder with hundreds of associated genes. Despite progress in the identification of the genetic causes of ID following the introduction of high-throughput sequencing, about half of affected individuals still remain without a molecular diagnosis. Consanguineous families with affected individuals provide a unique opportunity to identify novel recessive causative genes. In this report, we describe a novel autosomal recessive neurodevelopmental disorder. We identified two consanguineous families with homozygous variants predicted to alter the splicing of ATP9A which encodes a transmembrane lipid flippase of the class II P4-ATPases. The three individuals homozygous for these putatively truncating variants presented with severe ID, motor and speech impairment, and behavioral anomalies. Consistent with a causative role of ATP9A in these patients, a previously described Atp9a−/− mouse model showed behavioral changes.

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Homozygous missense WIPI2 variants cause a congenital disorder of autophagy with neurodevelopmental impairments of variable clinical severity and disease course

Brain Communications ◽

10.1093/braincomms/fcab183 ◽

2021 ◽

Author(s):

Reza Maroofian ◽

Andrea Gubas ◽

Rauan Kaiyrzhanov ◽

Marcello Scala ◽

Khalid Hundallah ◽

...

Keyword(s):

Intellectual Disability ◽

Neurodevelopmental Disorder ◽

Missense Variant ◽

Clinical Severity ◽

Global Developmental Delay ◽

Disease Course ◽

Single Family ◽

Ataxic Gait ◽

Related Disorder ◽

Autophagy Pathway

Abstract WIPI2 is a member of the human WIPI protein family (seven-bladed b-propeller proteins binding phosphatidylinositols, PROPPINs), which play a pivotal role in autophagy and has been implicated in the pathogenesis of several neurological conditions. The homozygous WIPI2 variant c.745G>A; p.(Val249Met) (NM_015610.4) has recently been associated with a neurodevelopmental disorder in a single family. Using exome sequencing and Sanger segregation analysis, here two novel homozygous WIPI2 variants (c.551T>G; p.(Val184Gly) and c.724C>T; p.(Arg242Trp) (NM_015610.4)) were identified in four individuals of two consanguineous families. Additionally, follow-up clinical data were sought from the previously reported family. Three non-ambulant affected siblings of the first family harboring the p.(Val184Gly) missense variant presented with microcephaly, profound global developmental delay/intellectual disability, refractory infantile/childhood-onset epilepsy, progressive tetraplegia with joint contractures, and dyskinesia. In contrast, the proband of the second family carrying the p.(Arg242Trp) missense variant, similar to the initially reported WIPI2 cases, presented with a milder phenotype, encompassing moderate intellectual disability, speech and visual impairment, autistic features, and an ataxic gait. Brain MR imaging in five patients showed prominent white matter involvement with a global reduction in volume, posterior corpus callosum hypoplasia, abnormal dentate nuclei, and hypoplasia of the inferior cerebellar vermis. To investigate the functional impact of these novel WIPI2 variants, we overexpressed both in WIPI2-knockout HEK293A cells. In comparison to wildtype, expression of the Val166Gly WIPI2b mutant resulted in a deficient rescue of LC3 lipidation whereas Arg224Trp mutant increased LC3 lipidation, in line with the previously reported Val231Met variant. These findings support a dysregulation of the early steps of the autophagy pathway. Collectively, our findings provide evidence that biallelic WIPI2 variants cause a neurodevelopmental disorder of variable severity and disease course. Our report expands the clinical spectrum and establishes WIPI2-related disorder as a congenital disorders of autophagy.

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