Biallelic loss‐of‐function NDUFA12 variants cause a wide phenotypic spectrum from Leigh/Leigh‐like syndrome to isolated optic atrophy

ANK3 related neurodevelopmental disorders: expanding the spectrum of heterozygous loss-of-function variants

Neurogenetics ◽

10.1007/s10048-021-00655-4 ◽

2021 ◽

Author(s):

Katja Kloth ◽

Bernarda Lozic ◽

Julia Tagoe ◽

Mariëtte J. V. Hoffer ◽

Amelie Van der Ven ◽

...

Keyword(s):

Autosomal Recessive ◽

Neuronal Development ◽

Autosomal Dominant ◽

Tissue Expression ◽

Autism Spectrum ◽

Loss Of Function ◽

Ankyrin G ◽

Phenotypic Spectrum ◽

And Function ◽

Neurodevelopmental Phenotype

AbstractANK3 encodes multiple isoforms of ankyrin-G, resulting in variegated tissue expression and function, especially regarding its role in neuronal development. Based on the zygosity, location, and type, ANK3 variants result in different neurodevelopmental phenotypes. Autism spectrum disorder has been associated with heterozygous missense variants in ANK3, whereas a more severe neurodevelopmental phenotype is caused by isoform-dependent, autosomal-dominant, or autosomal-recessive loss-of-function variants. Here, we present four individuals affected by a variable neurodevelopmental phenotype harboring a heterozygous frameshift or nonsense variant affecting all ANK3 transcripts. Thus, we provide further evidence of an isoform-based phenotypic continuum underlying ANK3-associated pathologies and expand its phenotypic spectrum.

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Phenotypic spectrum associated with CASK loss-of-function mutations

Journal of Medical Genetics ◽

10.1136/jmedgenet-2011-100218 ◽

2011 ◽

Vol 48 (11) ◽

pp. 741-751 ◽

Cited By ~ 76

Author(s):

U. Moog ◽

K. Kutsche ◽

F. Kortum ◽

B. Chilian ◽

T. Bierhals ◽

...

Keyword(s):

Loss Of Function ◽

Phenotypic Spectrum

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A Drosophila natural variation screen identifies NKCC1 as a substrate of NGLY1 deglycosylation and a modifier of NGLY1 deficiency

10.1101/2020.04.13.039651 ◽

2020 ◽

Author(s):

Dana M. Talsness ◽

Katie G. Owings ◽

Emily Coelho ◽

Gaelle Mercenne ◽

John M. Pleinis ◽

...

Keyword(s):

Developmental Delay ◽

Natural Variation ◽

Evolutionary Rate ◽

Phenotypic Variability ◽

Loss Of Function ◽

Ion Transporter ◽

Phenotypic Spectrum ◽

Mouse Cells ◽

Covariation Analysis ◽

Insight Into

AbstractN-Glycanase 1 (NGLY1) is a cytoplasmic deglycosylating enzyme. Loss-of-function mutations in the NGLY1 gene cause NGLY1 deficiency, which is characterized by developmental delay, seizures, and a lack of sweat and tears. To model the phenotypic variability observed among patients, we crossed a Drosophila model of NGLY1 deficiency onto a panel of genetically diverse strains. The resulting progeny showed a phenotypic spectrum from 0-100% lethality. Association analysis on the lethality phenotype as well as an evolutionary rate covariation analysis generated lists of modifying genes, providing insight into NGLY1 function and disease. The top association hit was Ncc69 (human NKCC1/2), a conserved ion transporter. Analyses in NGLY1 -/- mouse cells demonstrated that NKCC1 is misglycosylated and has reduced function, making it only the second confirmed NGLY1 enzymatic substrate. The misregulation of this ion transporter may explain the observed defects in secretory epithelium function in NGLY1 deficiency patients.

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A Drosophila screen identifies NKCC1 as a modifier of NGLY1 deficiency

eLife ◽

10.7554/elife.57831 ◽

2020 ◽

Vol 9 ◽

Author(s):

Dana M Talsness ◽

Katie G Owings ◽

Emily Coelho ◽

Gaelle Mercenne ◽

John M Pleinis ◽

...

Keyword(s):

Molecular Weight ◽

Evolutionary Rate ◽

Phenotypic Variability ◽

Average Molecular Weight ◽

Loss Of Function ◽

Ion Transporter ◽

Phenotypic Spectrum ◽

Mouse Cells ◽

Covariation Analysis ◽

Insight Into

N-Glycanase 1 (NGLY1) is a cytoplasmic deglycosylating enzyme. Loss-of-function mutations in the NGLY1 gene cause NGLY1 deficiency, which is characterized by developmental delay, seizures, and a lack of sweat and tears. To model the phenotypic variability observed among patients, we crossed a Drosophila model of NGLY1 deficiency onto a panel of genetically diverse strains. The resulting progeny showed a phenotypic spectrum from 0 to 100% lethality. Association analysis on the lethality phenotype, as well as an evolutionary rate covariation analysis, generated lists of modifying genes, providing insight into NGLY1 function and disease. The top association hit was Ncc69 (human NKCC1/2), a conserved ion transporter. Analyses in NGLY1-/- mouse cells demonstrated that NKCC1 has an altered average molecular weight and reduced function. The misregulation of this ion transporter may explain the observed defects in secretory epithelium function in NGLY1 deficiency patients.

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Novel Biallelic NSUN3 Variants Cause Early-Onset Mitochondrial Encephalomyopathy and Seizures

Journal of Molecular Neuroscience ◽

10.1007/s12031-020-01595-8 ◽

2020 ◽

Vol 70 (12) ◽

pp. 1962-1965

Author(s):

Arumugam Paramasivam ◽

Angamuthu K. Meena ◽

Challa Venkatapathi ◽

Robert D.S. Pitceathly ◽

Kumarasamy Thangaraj

Keyword(s):

Gene Expression ◽

Functional Analysis ◽

Mitochondrial Disease ◽

Early Onset ◽

Mitochondrial Encephalomyopathy ◽

The Novel ◽

Loss Of Function ◽

Chemical Modifications ◽

Phenotypic Spectrum ◽

Pathogenic Effects

Abstract Epitranscriptomic systems enable post-transcriptional modifications of cellular RNA that are essential for regulating gene expression. Of the ~ 170 known RNA chemical modifications, methylation is among the most common. Loss of function mutations in NSUN3, encoding the 5-methylcytosine (m5C) methyltransferase NSun3, have been linked to multisystem mitochondrial disease associated with combined oxidative phosphorylation deficiency. Here, we report a patient with early-onset mitochondrial encephalomyopathy and seizures in whom the novel biallelic NSUN3 missense variants c.421G>C (p.A141P) and c.454T>A (p.C152S) were detected. Segregation studies and in silico functional analysis confirmed the likely pathogenic effects of both variants. These findings expand the molecular and phenotypic spectrum of NSUN3-related mitochondrial disease.

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Brain calcifications and PCDH12 variants

Neurology Genetics ◽

10.1212/nxg.0000000000000166 ◽

2017 ◽

Vol 3 (4) ◽

pp. e166 ◽

Cited By ~ 7

Author(s):

Gaël Nicolas ◽

Monica Sanchez-Contreras ◽

Eliana Marisa Ramos ◽

Roberta R. Lemos ◽

Joana Ferreira ◽

...

Keyword(s):

Ct Scan ◽

Allele Frequency ◽

Minor Allele Frequency ◽

In Utero ◽

Adult Patients ◽

Loss Of Function ◽

Developmental Abnormalities ◽

Segregation Data ◽

Phenotypic Spectrum ◽

Brain Calcification

Objective:To assess the potential connection between PCDH12 and brain calcifications in a patient carrying a homozygous nonsense variant in PCDH12 and in adult patients with brain calcifications.Methods:We performed a CT scan in 1 child with a homozygous PCDH12 nonsense variant. We screened DNA samples from 53 patients with primary familial brain calcification (PFBC) and 26 patients with brain calcification of unknown cause (BCUC).Results:We identified brain calcifications in subcortical and perithalamic regions in the patient with a homozygous PCDH12 nonsense variant. The calcification pattern was different from what has been observed in PFBC and more similar to what is described in in utero infections. In patients with PFBC or BCUC, we found no protein-truncating variant and 3 rare (minor allele frequency <0.001) PCDH12 predicted damaging missense heterozygous variants in 3 unrelated patients, albeit with no segregation data available.Conclusions:Brain calcifications should be added to the phenotypic spectrum associated with PCDH12 biallelic loss of function, in the context of severe cerebral developmental abnormalities. A putative role for PCDH12 variants remains to be determined in PFBC.

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Loss-of-function HDAC8 mutations cause a phenotypic spectrum of Cornelia de Lange syndrome-like features, ocular hypertelorism, large fontanelle and X-linked inheritance

Human Molecular Genetics ◽

10.1093/hmg/ddu002 ◽

2014 ◽

Vol 23 (11) ◽

pp. 2888-2900 ◽

Cited By ~ 81

Author(s):

Frank J. Kaiser ◽

Morad Ansari ◽

Diana Braunholz ◽

María Concepción Gil-Rodríguez ◽

Christophe Decroos ◽

...

Keyword(s):

Cornelia De Lange Syndrome ◽

Loss Of Function ◽

Phenotypic Spectrum ◽

Ocular Hypertelorism ◽

Cornelia De Lange

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Delineating the molecular and phenotypic spectrum of the SETD1B-related syndrome

Genetics in Medicine ◽

10.1038/s41436-021-01246-2 ◽

2021 ◽

Author(s):

Marjolein J. A. Weerts ◽

Kristina Lanko ◽

Francisco J. Guzmán-Vega ◽

Adam Jackson ◽

Reshmi Ramakrishnan ◽

...

Keyword(s):

Intellectual Disability ◽

Developmental Delay ◽

Neurodevelopmental Disorder ◽

Epileptic Activity ◽

Language Delay ◽

Global Developmental Delay ◽

Sequence Variants ◽

Loss Of Function ◽

Phenotypic Spectrum

Abstract Purpose Pathogenic variants in SETD1B have been associated with a syndromic neurodevelopmental disorder including intellectual disability, language delay, and seizures. To date, clinical features have been described for 11 patients with (likely) pathogenic SETD1B sequence variants. This study aims to further delineate the spectrum of the SETD1B-related syndrome based on characterizing an expanded patient cohort. Methods We perform an in-depth clinical characterization of a cohort of 36 unpublished individuals with SETD1B sequence variants, describing their molecular and phenotypic spectrum. Selected variants were functionally tested using in vitro and genome-wide methylation assays. Results Our data present evidence for a loss-of-function mechanism of SETD1B variants, resulting in a core clinical phenotype of global developmental delay, language delay including regression, intellectual disability, autism and other behavioral issues, and variable epilepsy phenotypes. Developmental delay appeared to precede seizure onset, suggesting SETD1B dysfunction impacts physiological neurodevelopment even in the absence of epileptic activity. Males are significantly overrepresented and more severely affected, and we speculate that sex-linked traits could affect susceptibility to penetrance and the clinical spectrum of SETD1B variants. Conclusion Insights from this extensive cohort will facilitate the counseling regarding the molecular and phenotypic landscape of newly diagnosed patients with the SETD1B-related syndrome.

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The Analysis of Variants in the General Population Reveals That PMM2 Is Extremely Tolerant to Missense Mutations and That Diagnosis of PMM2-CDG Can Benefit from the Identification of Modifiers

International Journal of Molecular Sciences ◽

10.3390/ijms19082218 ◽

2018 ◽

Vol 19 (8) ◽

pp. 2218 ◽

Cited By ~ 16

Author(s):

Valentina Citro ◽

Chiara Cimmaruta ◽

Maria Monticelli ◽

Guglielmo Riccio ◽

Bruno Hay Mele ◽

...

Keyword(s):

General Population ◽

Autosomal Recessive ◽

Biochemical Analysis ◽

Autosomal Recessive Disease ◽

Type I ◽

Missense Mutations ◽

Loss Of Function ◽

Phenotype Correlation ◽

Phenotypic Spectrum ◽

Partial Deficiency

Type I disorders of glycosylation (CDG), the most frequent of which is phosphomannomutase 2 (PMM2-CDG), are a group of diseases causing the incomplete N-glycosylation of proteins. PMM2-CDG is an autosomal recessive disease with a large phenotypic spectrum, and is associated with mutations in the PMM2 gene. The biochemical analysis of mutants does not allow a precise genotype–phenotype correlation for PMM2-CDG. PMM2 is very tolerant to missense and loss of function mutations, suggesting that a partial deficiency of activity might be beneficial under certain circumstances. The patient phenotype might be influenced by variants in other genes associated with the type I disorders of glycosylation in the general population.

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