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Intellectual disability - microarray and sequencing v3.1519 FXN_GAA Sarah Leigh commented on STR: FXN_GAA
Intellectual disability - microarray and sequencing v3.1515 FXN_GAA Arina Puzriakova Source NHS GMS was added to STR: FXN_GAA.
Intellectual disability - microarray and sequencing v3.1074 FXN_GAA Sarah Leigh Phenotypes for STR: FXN_GAA were changed from Friedreich ataxia 229300 to Friedreich ataxia OMIM:229300; Friedreich ataxia with retained reflexes OMIM:229300; Friedreich ataxia 1 MONDO:0100340
Intellectual disability - microarray and sequencing v3.966 FXN_GAA Arina Puzriakova Tag curated_removed tag was added to STR: FXN_GAA.
Intellectual disability - microarray and sequencing v3.421 GAA Arina Puzriakova Source Expert Review Red was added to GAA.
Rating Changed from Amber List (moderate evidence) to Red List (low evidence)
Intellectual disability - microarray and sequencing v3.252 GAA Arina Puzriakova commented on gene: GAA
Intellectual disability - microarray and sequencing v3.170 HERC2 Konstantinos Varvagiannis edited their review of gene: HERC2: Added comment: Please consider upgrading this gene to green in the current panel based on the following updated review (13-07-2020):

Biallelic pathogenic HERC2 variants cause Mental retardation, autosomal recessive 38 (MIM 615516).

The current review is based mostly on the information provided by Elpidorou et al (2020 - PMID: 32571899) summarizing the findings in several affected individuals as published in the literature. ID was a universal feature among them (27/27) and seizures were reported in some (9/27):
- 22 subjects from Amish/Mennonite families were homozygous for p.Pro594Leu [NM_004667.5(HERC2):c.1781C>T] (Puffenberger et al 2012 - PMID: 23065719, Harlalka et al 2013 - PMID: 23243086, Abraham et al - PMID: 30902390)
- 2 additional patients were homozygous for another missense SNV [NM_004667.5(HERC2):c.4625G>A - p.Arg1542His] (Abraham et al 2019 - PMID: 30902390)
- 3 sibs born to consanguineous parents, homozygous for NM_004667.5:c.13767_13770delTGAA - p.(Asn4589LysTer4598)] as described by Elpidorou et al.
- 1 male homozygous 286 kb deletion spanning several 5' exons of HERC2 as well as the first exons of OCA2 was described by Morice-Picard et al (2016 - PMID: 27759030). Despite a neurological presentation (axial hypotonia, peripheral hypertonia, extrapyramidal symptoms and uncoordinated movements) further information was not available.

Apart from the cases summarized by Elpidorou et al, there have been few additional ones e.g. :
- Trujillano et al (2017 - PMID: 27848944) reported briefly on a patient, homozygous for NM_004667.5:c.4676-1G>A displaying seizures, hypotonia, global DD, "Encephalopathy" and abnormality of the liver.
- Yavarna et al (2015 - PMID: 26077850) provided few details with on an individual with primarily 'neurocognitive' phenotype but rather atypical presentation (MRI abnormalities, TGA, VSD, renal anomaly, growth retardation, hearing loss) due to p.Q3164X variant (recessive inheritance was specified).

Several lines of evidence support an important role for the protein encoded (an E3 ubiquitin protein ligase, interacting also with UBE3A, involved in several cellular processes incl. cell cycle regulation, spindle formation during mitosis, mitochondrial functions, DNA damage responses by targeting proteins such as XPA) as well as the effect of the reported variants (mRNA studies, Western blot, detection of a fusion transcript in the case of the deletion, etc).

Individuals from the Amish families displayed Angelman-like features (in line with HERC2-UBE3A interaction) with - among others - gait instability. Mouse models recapitulate some of these features (e.g. the movement disorder) as extensively discussed by Abraham et al.

Overall this gene can be included in the ID and epilepsy panels with green rating.

-----; Changed rating: GREEN; Changed publications: 23065719, 23243086, 30902390, 32571899, 27848944, 26077850, 27759030
Intellectual disability - microarray and sequencing v3.0 GAA Zornitza Stark reviewed gene: GAA: Rating: RED; Mode of pathogenicity: None; Publications: ; Phenotypes: ; Mode of inheritance: None
Intellectual disability - microarray and sequencing v2.573 FXN_GAA Louise Daugherty Classified STR: FXN_GAA as No list
Intellectual disability - microarray and sequencing v2.573 FXN_GAA Louise Daugherty Str: fxn_gaa has been removed from the panel.
Intellectual disability - microarray and sequencing v2.572 FXN_GAA Louise Daugherty Normal Number of Repeats for FXN_GAA was changed from 33 to 44.
Intellectual disability - microarray and sequencing GAA BRIDGE consortium edited their review of GAA
Intellectual disability - microarray and sequencing GAA BRIDGE consortium edited their review of GAA
Intellectual disability - microarray and sequencing GAA Louise Daugherty classified GAA as amber
Intellectual disability - microarray and sequencing GAA Louise Daugherty commented on GAA
Intellectual disability - microarray and sequencing GAA BRIDGE consortium reviewed GAA