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Intellectual disability

Gene: XPA

Amber List (moderate evidence)

XPA (XPA, DNA damage recognition and repair factor)
EnsemblGeneIds (GRCh38): ENSG00000136936
EnsemblGeneIds (GRCh37): ENSG00000136936
OMIM: 611153, Gene2Phenotype
XPA is in 14 panels

4 reviews

Caroline Wright (Sanger)

Red List (low evidence)

Phenotypes
XERODERMA PIGMENTOSUM, GROUP A

Rebecca Foulger (Genomics England curator)

I don't know

Included in the list of 528 known ID genes in Gilissen et al., 2014 (PMID:24896178) but no variants listed in Ligt et al., 2012 (PMID:23033978), which forms the basis for some of the Gilissen list. Sufficient XPA cases with mental retardation (>3) but relatedness is not always clear, and considerable variability for neurological phenotype between patients. Therefore rated Amber awaiting further cases.
Created: 29 Nov 2017, 11:19 a.m.
PMID:24135642 (2014) report 1 novel and 2 known XPA variants in 4 unrelated consanguineous Egyptian families (c.553C >T; p.Gln185, c.331G>T; p.Glu111 and c.374delC: p.Thr125Ilefs 15) with Xeroderma pigmentosum and mental retardation (phenotypically variable). For at least one of the variants, a Founder effect was proposed.
Created: 16 Oct 2017, 7:58 a.m.
PMID:25566891 report 13 patients from 10 families with XP. 4 distinct homozygous mutations in the XPA gene were seen in patients with moderate to severe mental retardation (6/10 families). The overlap between families is unclear: although the authors report that the families were unrelated, the variant c.335_338delTTATinsCATAAGAAA (p.F112SfsX2) was found in two unrelated families from Maharashtra (with the same family name) and founder effect was confirmed by haplotyping analysis. The mutation c. 428_429delAG (p.E143GfsX11) in exon 4 of XPA gene was also found in two unrelated families from Uttar Pradesh; haplotype analysis could not be performed for this mutation. No functional studies reported.
Created: 16 Oct 2017, 7:43 a.m.
PMID:26302748 present an 8 year old female patient from a consanguineous Iranian family with progressive intellectual impariment. Failure/delay in progressing through the normal developmental stages was evident since late infancy. She had microcephaly (OFC of 47 cm) and mental retardation. A novel homozygous frameshift mutation, c.349_353 delCTTAT (p.Leu117GlufsX4) in XPA was detected.
Created: 16 Oct 2017, 7:16 a.m.

Mode of inheritance
BIALLELIC, autosomal or pseudoautosomal

Phenotypes
mental retardation; progressive intellectual impariment

Publications

BRIDGE consortium (NIHRBR-RD)

Green List (high evidence)

This is a pertinent gene from the NIHR BioResource - Rare Diseases Study (NIHRBR-RD) BRIDGE Study : SPEED (Specialist Pathology: Evaluating Exomes in Diagnostics) which covers epilepsies, movement and microcephaly disorders, this gene is on the SPEED_NEURO_20170705 gene list. Evidences used for SPEED NEURO gene list: in_ddg2p_20141118_conf;in_ddg2p_20141118_conf;in_ddg2p_201507;in_ddg2p_201507_conf;in_ddg2p_2_4_2017;in_ddg2p_2_4_2017_conf;in_gilissen_2014_known . Main mutation mechanism : Loss of function
Created: 27 Jul 2017, 8:56 p.m.
Evidences key, gene present in following gene lists and main mutation mechanism : ddg2p_20141118; ddg2p_20141118_conf; ddg2p_201507; ddg2p_201507_conf; gilissen_2014_known; Nijmegen_ID_diagnostic; Nijmegen_ID_candidates; GEL_ID_red_20160217; neuro_20160418_strict; Loss of function. This is a pertinent gene from the BRIDGE Study : SPEED (Specialist Pathology: Evaluating Exomes in Diagnostics) which covers epilepsies, movement and microcephaly disorders, this gene comes from the SPEED_NEURO_v3.0_20170404 gene list. The following experts from the BRIDGE consortium NIHRBR-RD contributed to this panel: - Professor F. Lucy Raymond, Cambridge Institute for Medical Research, University of Cambridge - Manju Kurian, Paediatric neurologist, Great Ormond Street Hosptial - Keren Carss, NIHR BioResource - Rare Diseases, Cambridge University Hospitals NHS Foundation Trust - Alba Sanchis-Juan, NIHR BioResource - Rare Diseases, Cambridge University Hospitals NHS Foundation Trust - Marie Erwood NIHR BioResource - Rare Diseases, Cambridge University Hospitals NHS Foundation Trust - Louise Daugherty, NIHR BioResource - Rare Diseases, Cambridge University Hospitals NHS Foundation Trust
Created: 19 Jul 2017, 1:42 p.m.

Mode of inheritance
BIALLELIC, autosomal or pseudoautosomal

Publications

Lu Raymond (university of cambridge )

Red List (low evidence)

History Filter Activity

12 Mar 2018, Gel status: 2

Panel promoted to version 2.0

Ellen McDonagh (Genomics England Curator)

12.03.2018: Due to major updates completed (Phase 1, 2 and 3), this panel was promoted to Version 2 in order to reflect the major updates since November 2017 which have resulted in reviews for 836 genes added by Genomics England Curators and the Clinical Team, 130 new Green genes added to the interpretation pipeline (from 751 to 881 Green genes), and the gene total has increased from 1879 to 1927.

29 Nov 2017, Gel status: 2

Added New Source, Set mode of inheritance, Set publications

Ellen McDonagh (Genomics England Curator)

Expert Review Amber was added to XPA. Panel: Intellectual disability Model of inheritance for gene XPA was set to BIALLELIC, autosomal or pseudoautosomal Publications for gene XPA was set to ['26302748', ' 25566891', ' 24135642 ']

13 Nov 2015, Gel status: 1

gel status update

GEL ()

The Gel status was updated for this whole panel

13 Nov 2015, Gel status: 2

gel status update

GEL ()

The Gel status was updated for this whole panel

13 Nov 2015, Gel status: 1

Added New Source

Ellen McDonagh (Genomics England Curator)

XPA was added to Intellectual disabilitypanel. Source: Expert Review Red

24 Jun 2015, Gel status: 1

Added New Source

Ellen McDonagh (Genomics England Curator)

XPA was added to Intellectual disabilitypanel. Sources: Radboud University Medical Center, Nijmegen