Early onset or syndromic epilepsy
Gene: ATN1
Kept rating as Green based on Green post-Webex review from Helen Lord.Created: 9 Sep 2019, 10:14 a.m. | Last Modified: 9 Sep 2019, 10:14 a.m.
Panel Version: 1.312
Review and rating collated by Helen Lord (Oxford University Hospitals NHS Foundation Trust, 2019_08_30) on behalf of West Midlands, Oxford and Wessex GLH for GMS Neurology specialist test group. This gene was added to the Genetic epilepsy syndromes panel after the initial panel was reviewed by West Midlands, Oxford and Wessex GLH: this gene was therefore reviewed following the group Webex call on 2019_08_08 for Clinical Indication R59 Early onset or syndromic epilepsy.Created: 5 Sep 2019, 2:26 p.m. | Last Modified: 5 Sep 2019, 2:26 p.m.
Panel Version: 1.262
AD CHEDDA. Palmer et al 2019 (30827498) - 8 unrelated patients ranging in age from 2 months to 9 years with a similar neurodev disorder. 5/8 had overt seizures, incl 4 with severe infantile seizures, but all 8 had EEG abnormalities. 8 diff de novo het mutations identified all of which resulted in substitutions within the 16AA HX repeat motif. Nuclear magentic resonance analysis of a synthesised peptide containing one of these mutations - H1060Y - showed that the mutation resulted in a pertubation of the strucural and functional integrity of the HX repeat.Created: 5 Sep 2019, 2:22 p.m. | Last Modified: 5 Sep 2019, 2:22 p.m.
Panel Version: 1.261
Mode of inheritance
MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Mode of pathogenicity
Loss-of-function variants (as defined in pop up message) DO NOT cause this phenotype - please provide details in the comments
Comment on list classification: Advice from the clinical team at Genomics England on the rating of ATN1. (sic) "I don't have a problem with different mechanisms in a gene leading to slightly differing phenotypes and therefore different ratings on panels.
I would promote it to green as there are sufficient cases with an appropriate phenotype."
Therefore changing gene rating to Green.Created: 1 Jul 2019, 10:13 a.m. | Last Modified: 1 Jul 2019, 10:13 a.m.
Panel Version: 0.45
Konstantinos Varvagiannis reviewed Palmer et al. (2019 - PMID: 30827498) who describes 8 individuals all with de novo variants in a specific and highly evolutionary conserved histidine-rich 16 amino acid motif encoded by exon 7 of ATN1. The pedigree analysis showed that all individuals are unrelated with different ancestry, all except one had undergone trio sequencing.
All individuals have DD/ID and 5/8 have seizures therefore making it applicable to the epilepsy panel. ATN1 is in OMIM but is associated with the STR, it is in Gene2Phenotype as probable based on this paper.
ATN1_CAG STR is Green in a large number of panels and there are a number of publications associated with the STR. This is the first publication where variants within the gene and not the STR have been associated with this phenotype.Created: 25 Jun 2019, 10:50 a.m. | Last Modified: 1 Jul 2019, 10:17 a.m.
Panel Version: 0.45
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: LiteratureCreated: 8 Mar 2019, 6:47 p.m.
Mode of inheritance
MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Phenotypes
Generalized hypotonia; Global developmental delay; Intellectual disability; Seizures; Feeding difficulties; Abnormality of the cardiovascular system; Cleft palate; Abnormality of the kidney
Publications
Mode of pathogenicity
Loss-of-function variants (as defined in pop up message) DO NOT cause this phenotype - please provide details in the comments
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
Source Wessex and West Midlands GLH was added to ATN1.
Source NHS GMS was added to ATN1.
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
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
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)
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