Variants in ADD1 Cause Intellectual Disability, Corpus Callosum Dysgenesis, and Ventriculomegaly in Humans

Cai, Qingsong; Feng, Irena; Costa, Ana Rita; Pinto‐Costa, Rita; Neil, Jennifer E.; Caluseriu, Oana; Bupp, Caleb; Andersen, Charlotte Brasch; Fagerberg, Christina; Ruan, Xiangbin; Kang, Bowei; Hu, Kaining; Zhong, Rong; Brites, Pedro; Liu, Dong; Bhoj, Elizabeth; Hill, Robert S.; Kahle, Kristopher T.; Sousa, Mónica Mendes; Walsh, Christopher A.; Zhang, Xiaochang

doi:10.2139/ssrn.3931622

Cited by 2 publications

(2 citation statements)

References 40 publications

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“…Although adducin is primarily responsible for the assembly of spectrin-actin that provides functional support to the cytoskeleton, the gene ontology also annotates the gene to ion transport and synaptic functions. Variants in ADD1 have also been recently identified in intellectual disability, corpus callosum dysgenesis, and ventriculomegaly in humans 36 . Similarly, ATM, another gene with QRVs for NAFE, has been recently shown to be involved in hippocampal and cortical development, as well as synaptic functions 37 .…”

Section: Enrichment Of Qrvs In Three Types Of Epilepsiesmentioning

confidence: 97%

The role of rare genetic variants enrichment in epilepsies of presumed genetic etiology

Bundalian

Chen

et al. 2023

Preprint

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Previous studies suggested that severe epilepsies e.g., developmental and epileptic encephalopathies (DEE) are mainly caused by ultra-rare de novo genetic variants. For milder phenotypes, rare genetic variants could contribute to the phenotype. To determine the importance of rare variants for different epilepsy types, we analyzed a whole-exome sequencing cohort of 9,170 epilepsy-affected individuals and 8,436 controls. Here, we separately analyzed three different groups of epilepsies: severe DEEs, genetic generalized epilepsy (GGE), and non-acquired focal epilepsy (NAFE). We required qualifying rare variants (QRVs) to occur in controls at a minor allele frequency ≤ 1:1,000, to be predicted as deleterious (CADD≥20), and to have an odds ratio in epilepsy cases ≥2. We identified genes enriched with QRVs in DEE (n=21), NAFE (n=72), and GGE (n=32). Enrichment was strongest in NAFE and weakest in DEE. This suggests that rare variants may play a more important role for causality of NAFE than in DEE. Moreover, we found that QRV-carrying genes e.g., HSGP2, FLNA or TNC are involved in structuring the brain extracellular matrix. The present study confirms an involvement of rare variants for NAFE, while in DEE and GGE, the contribution of such variants appears more limited.

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Section: Enrichment Of Qrvs In Three Types Of Epilepsiesmentioning

confidence: 97%

The role of rare genetic variants enrichment in epilepsies of presumed genetic etiology

Bundalian

Chen

et al. 2023

Preprint

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“…Furthermore, a p.Gly47Arg variant was found in two sisters with Ritscher-Schinzel syndrome (Jeanne et al, 2021). It is critical to note that all individuals with p.Glu41Lys and p.Gly47Arg mutations in DPYSL5 display an agenesis of corpus callosum which is a neuroanatomical malformation already associated with ASD and ID (Halgren et al, 2012;Wegiel et al, 2018;Li et al, 2019;Mimura et al, 2019;Nabais Sá et al, 2020;Qi et al, 2022).…”

Section: Genetic Variants In Dpysl5mentioning

confidence: 99%

Contribution of the dihydropyrimidinase-like proteins family in synaptic physiology and in neurodevelopmental disorders

et al. 2023

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The dihydropyrimidinase-like (DPYSL) proteins, also designated as the collapsin response mediators (CRMP) proteins, constitute a family of five cytosolic phosphoproteins abundantly expressed in the developing nervous system but down-regulated in the adult mouse brain. The DPYSL proteins were initially identified as effectors of semaphorin 3A (Sema3A) signaling and consequently involved in regulation of growth cone collapse in young developing neurons. To date, it has been established that DPYSL proteins mediate signals for numerous intracellular/extracellular pathways and play major roles in variety of cellular process including cell migration, neurite extension, axonal guidance, dendritic spine development and synaptic plasticity through their phosphorylation status. The roles of DPYSL proteins at early stages of brain development have been described in the past years, particularly for DPYSL2 and DPYSL5 proteins. The recent characterization of pathogenic genetic variants in DPYSL2 and in DPYSL5 human genes associated with intellectual disability and brain malformations, such as agenesis of the corpus callosum and cerebellar dysplasia, highlighted the pivotal role of these actors in the fundamental processes of brain formation and organization. In this review, we sought to establish a detailed update on the knowledge regarding the functions of DPYSL genes and proteins in brain and to highlight their involvement in synaptic processing in later stages of neurodevelopment, as well as their particular contribution in human neurodevelopmental disorders (NDDs), such as autism spectrum disorders (ASD) and intellectual disability (ID).

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Variants in ADD1 Cause Intellectual Disability, Corpus Callosum Dysgenesis, and Ventriculomegaly in Humans

Cited by 2 publications

References 40 publications

The role of rare genetic variants enrichment in epilepsies of presumed genetic etiology

The role of rare genetic variants enrichment in epilepsies of presumed genetic etiology

Contribution of the dihydropyrimidinase-like proteins family in synaptic physiology and in neurodevelopmental disorders

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