Deciphering the molecular landscape of microcephaly in 87 Indian families by exome sequencing

Masih, Suzena; Moirangthem, Amita; Shambhavi, Arya; Rai, Archana; Mandal, Kausik; Saxena, Deepti; Nilay, Mayank; Agrawal, Neha; Srivastava, Somya; Sait, Haseena; Phadke, Shubha R.

doi:10.1016/j.ejmg.2022.104520

Cited by 6 publications

(4 citation statements)

References 39 publications

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“… Pathogenic mutations in human ANKLE2 associated with primary congenital microcephaly. Schematic of human ANKLE2 protein structure showing sites of known pathogenic mutations, as originally described ( Yamamoto et al, 2014 ; Link et al, 2019 ; Shaheen et al, 2019 ; Masih et al, 2022 ; Thomas et al, 2022 ). Point mutations leading to missense mutations are shown in black, mutations leading to protein truncations are shown in red.…”

Section: Roles Of Ankle2 In Human Diseasementioning

confidence: 99%

“…Additional studies have expanded the range of ANKLE2 mutations and allele combinations associated with this disease ( Fig. 4 and Table 1 ) ( Link et al, 2019 ; Masih et al, 2022 ; Thomas et al, 2022 ). Other studies have also implicated mutations of VRK1 ( Shaheen et al, 2019 ) and ZFP335 ( Yang et al, 2012 ) in MCPH, further supporting a role for the ANKLE2 pathway in neurodevelopment.…”

Section: Roles Of Ankle2 In Human Diseasementioning

confidence: 99%

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Molecular functions of ANKLE2 and its implications in human disease

Fishburn,

Florio,

Lopez

et al. 2024

Disease Models &Amp; Mechanisms

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Ankyrin repeat and LEM domain-containing 2 (ANKLE2) is a scaffolding protein with established roles in cell division and development, the dysfunction of which is increasingly implicated in human disease. ANKLE2 regulates nuclear envelope disassembly at the onset of mitosis and its reassembly after chromosome segregation. ANKLE2 dysfunction is associated with abnormal nuclear morphology and cell division. It regulates the nuclear envelope by mediating protein-protein interactions with barrier to autointegration factor (BANF1; also known as BAF) and with the kinase and phosphatase that modulate the phosphorylation state of BAF. In brain development, ANKLE2 is crucial for proper asymmetric division of neural progenitor cells. In humans, pathogenic loss-of-function mutations in ANKLE2 are associated with primary congenital microcephaly, a condition in which the brain is not properly developed at birth. ANKLE2 is also linked to other disease pathologies, including congenital Zika syndrome, cancer and tauopathy. Here, we review the molecular roles of ANKLE2 and the recent literature on human diseases caused by its dysfunction.

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Section: Roles Of Ankle2 In Human Diseasementioning

confidence: 99%

Section: Roles Of Ankle2 In Human Diseasementioning

confidence: 99%

Molecular functions of ANKLE2 and its implications in human disease

Fishburn,

Florio,

Lopez

et al. 2024

Disease Models &Amp; Mechanisms

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“…1c). Importantly, WES analysis of a large cohort of patients with microcephaly identified a male patient of North Indian ancestry (patient F46.1) with another homozygous splice variant in intron 5 of ATRIP (c.829+2T>G) 39 . He presented with similar phenotypic features of facial dysmorphism, short stature, microcephaly, moderate ID, and recurrent RTIs (Supplementary Fig.…”

Section: Homozygous Intronic Atrip Variants In Patients With Mpd and ...mentioning

confidence: 99%

ATRIP deficiency impairs the replication stress response and manifests as microcephalic primordial dwarfism and immunodeficiency

Duthoo,

Beyls,

Backers

et al. 2024

Preprint

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ATR (Ataxia Telangiectasia and Rad3-related) kinase and its interacting protein ATRIP orchestrate the replication stress response. Two patients of independent ancestry with microcephaly, primordial dwarfism, and recurring infections were found to be homozygous for splice donor site variants of ATRIP exon 5, resulting in ATRIP deficiency. The c.829+5G>T patient exhibited autoimmune hemolytic anemia, lymphopenia, poor vaccine response, and intermittent neutropenia. Immunophenotyping revealed reduced CD16+ NK cells and absent naïve T cells, mucosal-associated invariant T cells (MAITs), and invariant natural killer T cells (iNKTs). Lymphocytic defects were characterized by T cell receptor (TCR) oligoclonality, abnormal class switch recombination (CSR), and impaired T cell proliferation. ATRIP deficiency resulted in low-grade ATR activation but impaired CHK1 phosphorylation upon genotoxic stress. Consequently, ATRIP deficient cells inadequately regulated DNA replication, leading to chromosomal instability, compromised cell cycle control, and impaired cell viability. CRISPR-SelectTIME confirmed reduced cell fitness induced by both variants. This study establishes ATRIP deficiency as a monogenic cause of microcephalic primordial dwarfism, highlights ATRIP′s critical role in protecting immune cells from replication stress, and brings a renewed perspective to the canonical functions of ATRIP.

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“…3,[5][6][7] ES/GS has been found to have similar yield and benefits among individuals with other pediatriconset neurologic conditions including cerebral palsy, neuromuscular disorders, and microcephaly. 8,9,10 Though ES/GS have the highest diagnostic yield compared to other genetic tests, 11,12 they are often not easily accessible due to barriers including insurance coverage, out of pocket cost, and access to specialists/genetic counselors. [13][14][15][16] In many cases, referral to genetics specialists is required for patients to obtain ES/GS.…”

Section: Introductionmentioning

confidence: 99%

Social Determinants of Genetics Referral and Completion Rates Among Child Neurology Patients

Cole,

Sellitto,

Baratta

et al. 2023

Preprint

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ObjectiveTo investigate clinical, social, and systems-level determinants predictive of genetics clinic referral and completion of genetics clinic visits among child neurology patients.MethodsElectronic health record data were extracted from patients 0-18 years old who were evaluated in child neurology clinics at a single tertiary care institution between July 2018 to January 2020. Variables aligned with the Health Equity Implementation Framework. Referral and referral completion rates to genetics and cardiology clinics were compared among Black vs White patients using bivariate analysis. Demographic variables associated with genetics clinic referral and visit completion were identified using logistic regressions.ResultsIn a cohort of 11,371 child neurology patients, 304 genetics clinic referrals and 82 cardiology clinic referrals were placed. In multivariate analysis of patients with Black or White ethnoracial identity (n=10,601), genetics clinic referral rates did not differ by race, but were significantly associated with younger age, rural address, neurodevelopmental disorder diagnosis, number of neurology clinic visits, and provider type. The only predictors of genetics clinic visit completion number of neurology clinic visits and race/ethnicity, with White patients being twice as likely as Black patients to complete the visit. Cardiology clinic referrals and visit completion did not differ by race/ethnicity.InterpretationAlthough race/ethnicity was not associated with differences in genetics clinic referral rates, White patients were twice as likely as Black patients to complete a genetics clinic visit after referral. Further work is needed to determine whether this is due to systemic/structural racism, differences in attitudes toward genetic testing, or other factors.

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Deciphering the molecular landscape of microcephaly in 87 Indian families by exome sequencing

Cited by 6 publications

References 39 publications

Molecular functions of ANKLE2 and its implications in human disease

Molecular functions of ANKLE2 and its implications in human disease

ATRIP deficiency impairs the replication stress response and manifests as microcephalic primordial dwarfism and immunodeficiency

Social Determinants of Genetics Referral and Completion Rates Among Child Neurology Patients

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