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Early onset or syndromic epilepsy v2.498 ATN1_CAG Ivone Leong commented on STR: ATN1_CAG
Early onset or syndromic epilepsy v2.496 ATN1_CAG Arina Puzriakova Classified STR: ATN1_CAG as Green List (high evidence)
Early onset or syndromic epilepsy v2.496 ATN1_CAG Arina Puzriakova Str: atn1_cag has been classified as Green List (High Evidence).
Early onset or syndromic epilepsy v2.493 ATN1_CAG Arina Puzriakova Normal Number of Repeats for ATN1_CAG was changed from 35 to 36.
Rating Changed from Green List (high evidence) to Red List (low evidence)
Early onset or syndromic epilepsy v2.459 ATN1_CAG Arina Puzriakova Phenotypes for STR: ATN1_CAG were changed from Dentatorubro-pallidoluysian atrophy 125370 to Dentatorubral-pallidoluysian atrophy, OMIM:125370
Early onset or syndromic epilepsy v2.458 ATN1 Arina Puzriakova Phenotypes for gene: ATN1 were changed from Congenital hypotonia, epilepsy, developmental delay, and digital anomalies, 618494; Global developmental delay; Intellectual disability; Seizures; Generalized hypotonia to Congenital hypotonia, epilepsy, developmental delay, and digital anomalies, OMIM:618494
Early onset or syndromic epilepsy v1.331 ATN1 Rebecca Foulger Source Wessex and West Midlands GLH was added to ATN1.
Early onset or syndromic epilepsy v1.330 ATN1 Rebecca Foulger Source NHS GMS was added to ATN1.
Early onset or syndromic epilepsy v1.312 ATN1 Rebecca Foulger commented on gene: ATN1: Kept rating as Green based on Green post-Webex review from Helen Lord.
Early onset or syndromic epilepsy v1.312 ATN1 Rebecca Foulger Phenotypes for gene: ATN1 were changed from Congenital hypotonia, epilepsy, developmental delay, and digital anomalies, 618494; Global developmental delay; Intellectual disability; Seizures to Congenital hypotonia, epilepsy, developmental delay, and digital anomalies, 618494; Global developmental delay; Intellectual disability; Seizures; Generalized hypotonia
Early onset or syndromic epilepsy v1.311 ATN1 Rebecca Foulger Phenotypes for gene: ATN1 were changed from Abnormality of the kidney; Seizures; Hypotonia; Cleft palate; Developmental Delay; Abnormality of the cardiovascular system; Epilepsy; Generalized hypotonia; Feeding difficulties; Intellectual disability; Global developmental delay; Digit Abnormalities to Congenital hypotonia, epilepsy, developmental delay, and digital anomalies, 618494; Global developmental delay; Intellectual disability; Seizures
Early onset or syndromic epilepsy v1.262 ATN1 Rebecca Foulger reviewed gene: ATN1: Rating: AMBER; Mode of pathogenicity: ; Publications: ; Phenotypes: ; Mode of inheritance:
Early onset or syndromic epilepsy v1.261 ATN1 Helen Lord reviewed gene: ATN1: Rating: GREEN; Mode of pathogenicity: Loss-of-function variants (as defined in pop up message) DO NOT cause this phenotype - please provide details in the comments; Publications: ; Phenotypes: ; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Early onset or syndromic epilepsy v1.193 ATN1_CAG Rebecca Foulger Source NHS GMS was added to STR: ATN1_CAG.
Early onset or syndromic epilepsy v1.191 ATN1_CAG Rebecca Foulger commented on STR: ATN1_CAG
Early onset or syndromic epilepsy v1.177 ATN1 Catherine Snow Source Expert Review Green was added to ATN1.
Source Expert Review was added to ATN1.
Added phenotypes Hypotonia; Epilepsy; Digit Abnormalities; Developmental Delay for gene: ATN1
Rating Changed from No List (delete) to Green List (high evidence)
Early onset or syndromic epilepsy v1.30 ATN1 Konstantinos Varvagiannis gene: ATN1 was added
gene: ATN1 was added to Genetic epilepsy syndromes. Sources: Literature
Mode of inheritance for gene: ATN1 was set to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Publications for gene: ATN1 were set to 30827498
Phenotypes for gene: ATN1 were set to Generalized hypotonia; Global developmental delay; Intellectual disability; Seizures; Feeding difficulties; Abnormality of the cardiovascular system; Cleft palate; Abnormality of the kidney
Penetrance for gene: ATN1 were set to unknown
Mode of pathogenicity for gene: ATN1 was set to Loss-of-function variants (as defined in pop up message) DO NOT cause this phenotype - please provide details in the comments
Review for gene: ATN1 was set to GREEN
Added comment: Apart from CAG repeat expansions (green in the present panel) seizures have been reported in individuals with mutations in the HX repeat motif (5 unrelated individuals, each with a private variant).

As a result, ATN1 can be considered for inclusion in the Epilepsy panel as green (or amber).

Copied from the ID panel :

Palmer et al. (2019 - PMID: 30827498) report on 8 individuals all harboring de novo missense or insertion variants within a 16-amino-acid HX repeat motif (aa 1150-1065 / 8 HX repeats, where H is histidine and X any amino acid) in exon 7 of ATN1. The specific motif is distal to the Gln-rich region involved in Dentatorubro-pallidoluysian atrophy (caused by polyglutamine expansion in exon 5, due to a probable toxic GoF effect - MIM #125370). None of the subjects reported presented features of the latter disorder.

Common features included hypotonia (8/8) , DD and/or ID (8/8). Other frequent features included visual or hearing impairment, seizures (5/8 - in most presenting as neonatal/infantile onset dev. encephalopathy), feeding difficulties/functional GI disorders. Some individuals presented with congenital anomalies eg. cardiac, cleft palate, renal anomalies, anteriorly placed anus. Some facial (eg. presence of tall forehead, bitemporal narrowing, deep set eyes, sparse lateral hair, bulbous nose, open mouth appearance ,etc) or features of the extremities (overlapping fingers/toes) were also common.

Converging evidence from the literature suggests that ATN1 is a nuclear transcriptional regulator important in the control of brain and other organ development (PMIDs cited: 17150957, 25519973, 10973986). The gene is widely expressed in various tissues incl. brain, heart, lung, kidney, skeletal muscle. Expression is higher in fetal tissues particularly in brain while the gene is broadly expressed in multiple regions of the adult human brain (PMID: 7485154).

All 8 variants were missense SNVs or insertions within the HX repeat motif (aa 1150-1065) and had occurred as de novo events: c.3160C>A or p.His1054Asn, c.3172C>T or p.His1058Tyr, c.3177_3178insAACCTG or p.Ser1059_His1060insAsnLeu, c.3177_3178insGACCTG or p.Ser1059_His1060insAspLeu, c.3178C>T or p.His1060Tyr, c.3184C>G or p.His1062Asp, c.3188T>G or p.Leu1063Arg, c.3185A>G or p.His1062Arg [NM_001007026.1].

NMR studies of 2 commercialy synthesized polypeptides containing residues 1046-1067 of ATN1 and the HX motif suggested disruption in the case of His1060Tyr of the spatial and dynamical synchronization of histidines which is favored by the regularly spaced occurrence of histidines in the wild-type sequence. Under specific conditions introduction of His1060Tyr allowed zinc binding, which was not the case for the wild-type peptide, thus conferring the peptide a novel property (the consequences of which are though unknown). Clustering of the variants and presence of LoF in healthy individuals (eg. in gnomAD db) suggests that haploinsufficiency is unlikely.

Similar (HX)n repeat motifs exist in other proteins, among others RERE or AUTS2 which are associated with neurodevelopmental disorders. The authors comment that disruption of the HX motif in RERE has been reported in affected individuals and that mutations occurring in this motif are more likely to be associated with congenital anomalies, compared to mutations in the rest of the protein.

As for animal models, Atn1 -/- mice are neurologically normal. Knockdown of the gene in rat neuronal progenitor cells led to anomalies in brain development, though these could be rescued by co-transfection with human ATN1 construct (PMIDs cited: 17150957, 25519973).
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In OMIM, heterozygous pathogenic CAG trinucleotide expansions in ATN1 are associated with DRPLA (MIM #125370). The gene is not associated with any phenotype in G2P.
Sources: Literature
Early onset or syndromic epilepsy v1.6 ATN1_CAG Louise Daugherty GRCh38 position for ATN1_CAG was changed from 6936717-6936742 to 6936717-6936772.
Rating Changed from Green List (high evidence) to Green List (high evidence)
Early onset or syndromic epilepsy v0.1487 ATN1_CAG Arianna Tucci Phenotypes for STR: ATN1_CAG were changed from to Dentatorubro-pallidoluysian atrophy 125370
Early onset or syndromic epilepsy v0.1413 ATN1_CAG Louise Daugherty Tag STR tag was added to STR: ATN1_CAG.
Early onset or syndromic epilepsy v0.1406 ATN1_CAG Arianna Tucci Marked STR: ATN1_CAG as ready
Early onset or syndromic epilepsy v0.1406 ATN1_CAG Arianna Tucci Str: atn1_cag has been classified as Green List (High Evidence).
Early onset or syndromic epilepsy v0.1406 ATN1_CAG Arianna Tucci Classified STR: ATN1_CAG as Green List (high evidence)
Early onset or syndromic epilepsy v0.1406 ATN1_CAG Arianna Tucci Str: atn1_cag has been classified as Green List (High Evidence).
Early onset or syndromic epilepsy v0.1405 ATN1_CAG Arianna Tucci STR: ATN1_CAG was added
STR: ATN1_CAG was added to Genetic epilepsy syndromes. Sources: Expert Review
Mode of inheritance for STR: ATN1_CAG was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Review for STR: ATN1_CAG was set to GREEN
Added comment: Sources: Expert Review