Haploinsufficiency of ARFGEF1 is associated with developmental delay, intellectual disability, and epilepsy with variable expressivity

Quentin, Thomas; Gautier, Thierry; Marafi, Dana; Besnard, Thomas; Willems, Marjolaine; Moutton, Sébastien; Isidor, B.; Cogné, Benjamin; Conrad, Solène; Tenconi, Romano; Iascone, Maria; Sorlin, Arthur; Masurel, Alice; Dabir, Tabib; Jackson, Adam; Banka, Siddharth; Delanne, Julian; Lupski, James R.; Saadi, Nebal Waill; Alkuraya, Fowzan S.; Zahrani, Fatema Al; Agrawal, Pankaj B.; England, Eleina; Madden, Jill A.; Posey, Jennifer E.; Bürglen, Lydie; Chevarin, Martin; Nguyen, Sylvie; Mau-Them, Frédéric Tran; Duffourd, Yannis; Garret, Philippine; Bruel, Ange‐Line; Callier, Patrick; Marle, Nathalie; Wieczorek, Dagmar; Duplomb, Laurence; Philippe, Christophe; Thauvin‐Robinet, Christel; Govin, Jérôme; Faivre, Laurence; Vitobello, Antonio

doi:10.1038/s41436-021-01218-6

Cited by 10 publications

(12 citation statements)

References 40 publications

(35 reference statements)

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“…Males are two to four times as likely than females to acquire neurodevelopmental disorders (May et al, 2019). The authors of the paper by Thomas et al (2021) noticed an unbalanced sex ratio of the diseases but were unsure if this was due to an actual sex-dependent incidence or in their cohort by chance. We found an uneven sex ratio in our cohort (four males and one female); therefore, we agree with Thomas et al that the illnesses have a true sex-dependent incidence.…”

Section: Discussionmentioning

confidence: 99%

“…Teoh et al (2019) reported an ARFGEF1 nonsense variant in a patient with Lennox-Gastaut syndrome. Another recent study revealed ARFGEF1 heterozygous truncating variants in 13 patients from 11 families with a novel developmental delay condition caused by haploinsufficiency (Thomas et al, 2021; without a MIM# assigned at the time of manuscript preparation).…”

Section: Introductionmentioning

confidence: 99%

“…However, before this publication, no more than 15 pathogenic ARFGEF1 variants had been reported in peer-reviewed papers in the ClinVar database, making the interpretation of ARFGEF1 variants problematic. The mutations result in null alleles, with just one proven pathogenic missense mutation (Thomas et al, 2021) and overlook any additional disease-causing missense mutations. Furthermore, in the study of Thomas et al (2021), low-penetrance mutations (c.4033C>T and c.3697C>T) of ARFGEF1 were discovered, and all the preceding mutations in non-Asian populations.…”

Section: Introductionmentioning

confidence: 99%

“…The mutations result in null alleles, with just one proven pathogenic missense mutation (Thomas et al, 2021) and overlook any additional disease-causing missense mutations. Furthermore, in the study of Thomas et al (2021), low-penetrance mutations (c.4033C>T and c.3697C>T) of ARFGEF1 were discovered, and all the preceding mutations in non-Asian populations. More importantly, determining if variants cause a particular disease in a specific gene requires more replication in other unrelated but similarly affected patients.…”

Section: Introductionmentioning

confidence: 99%

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Expanding the Phenotypic and Genotypic Spectrum of ARFGEF1-Related Neurodevelopmental Disorder

Zhang²,

Ren³

et al. 2022

Front. Mol. Neurosci.

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Mono-allelic loss-of-function variants in ARFGEF1 have recently caused a developmental delay, intellectual disability, and epilepsy, with varying clinical expressivity. However, given the clinical heterogeneity and low-penetrance mutations of ARFGEF1-related neurodevelopmental disorder, the robustness of the gene-disease association requires additional evidence. In this study, five novel heterozygous ARFGEF1 variants were identified in five unrelated pediatric patients with neurodevelopmental disorders, including one missense change (c.3539T>G), two canonical splice site variants (c.917-1G>T, c.2850+2T>A), and two frameshift (c.2923_c.2924delCT, c.4951delG) mutations resulting in truncation of ARFGEF1. The pathogenic/likely pathogenic variants presented here will be highly beneficial to patients undergoing genetic testing in the future by providing an expanded reference list of disease-causing variants.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 2 more Smart Citations

Expanding the Phenotypic and Genotypic Spectrum of ARFGEF1-Related Neurodevelopmental Disorder

Zhang²,

Ren³

et al. 2022

Front. Mol. Neurosci.

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“…The genotype‐linked phenotypic data allows, for example, new variant‐disease associations to be discovered, such as loss‐of‐function variants in ARFGEF1 causing developmental delay and epilepsy (Thomas et al, 2021 ). The data set also enables the extension of phenotypes for new syndromes to be uncovered (e.g., Witteveen–Kolk syndrome a SIN3A ‐related disorder; Balasubramanian et al, 2021 ), in addition to well‐established syndromes (e.g., ALG13 congenital disorder of glycosylation; Alsharhan et al, 2021 ).…”

Section: Driving Rare Disease Researchmentioning

confidence: 99%

DECIPHER: Supporting the interpretation and sharing of rare disease phenotype‐linked variant data to advance diagnosis and research

et al. 2022

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DECIPHER (https://www.deciphergenomics.org) is a free web platform for sharing anonymized phenotype‐linked variant data from rare disease patients. Its dynamic interpretation interfaces contextualize genomic and phenotypic data to enable more informed variant interpretation, incorporating international standards for variant classification. DECIPHER supports almost all types of germline and mosaic variation in the nuclear and mitochondrial genome: sequence variants, short tandem repeats, copy‐number variants, and large structural variants. Patient phenotypes are deposited using Human Phenotype Ontology (HPO) terms, supplemented by quantitative data, which is aggregated to derive gene‐specific phenotypic summaries. It hosts data from >250 projects from ~40 countries, openly sharing >40,000 patient records containing >51,000 variants and >172,000 phenotype terms. The rich phenotype‐linked variant data in DECIPHER drives rare disease research and diagnosis by enabling patient matching within DECIPHER and with other resources, and has been cited in >2,600 publications. In this study, we describe the types of data deposited to DECIPHER, the variant interpretation tools, and patient matching interfaces which make DECIPHER an invaluable rare disease resource.

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A genome‐wide association study of morphometric traits in dromedaries

Sani

Karimi

Burger³

et al. 2023

Veterinary Medicine & Sci

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Background: Investigating genomic regions associated with morphometric traits in camels is valuable, because it allows a better understanding of adaptive and productive features to implement a sustainable management and a customised breeding program for dromedaries.Objectives: With a genome-wide association study (GWAS) including 96 Iranian dromedaries phenotyped for 12 morphometric traits and genotyped-by-sequencing (GBS) with 14,522 SNPs, we aimed at identifying associated candidate genes. Methods:The association between SNPs and morphometric traits was investigated using a linear mixed model with principal component analysis (PCA) and kinship matrix.Results: With this approach, we detected 59 SNPs located in 37 candidate genes potentially associated to morphometric traits in dromedaries. The top associated SNPs were related to pin width, whither to pin length, height at whither, muzzle girth, and tail length. Interestingly, the results highlight the association between whither height, muzzle circumference, tail length, whither to pin length. The identified candidate genes were associated with growth, body size, and immune system in other species. Conclusions: We identified three key hub genes in the gene network analysis including ACTB, SOCS1 and ARFGEF1. In the central position of gene network, ACTB was detected as the most important gene related to muscle function. With this initial This is an open access article under the terms of the Creative Commons Attribution License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited.

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Haploinsufficiency of ARFGEF1 is associated with developmental delay, intellectual disability, and epilepsy with variable expressivity

Cited by 10 publications

References 40 publications

Expanding the Phenotypic and Genotypic Spectrum of ARFGEF1-Related Neurodevelopmental Disorder

Expanding the Phenotypic and Genotypic Spectrum of ARFGEF1-Related Neurodevelopmental Disorder

DECIPHER: Supporting the interpretation and sharing of rare disease phenotype‐linked variant data to advance diagnosis and research

A genome‐wide association study of morphometric traits in dromedaries

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