Intellectual disability - microarray and sequencing
Gene: ATP6AP2Comment on list classification: Changed from Amber to Green. From external review comment and further publications to support gene-disease association. There are more than three unrelated cases and pathogenic variants for X-linked intellectual disability, Hedera type (PMID:26467484;11782983 15746149; 29127204).Created: 13 Aug 2018, 3:27 p.m.
Comment on publications: added publication PMID:29127204 (2017) suggested by external reviewer with functional evidence on more variants support the rating of this gene to be promoted to Green. Two hemizygous mutations in ATP6AP2 were identified by whole exome sequencing in three male individuals from two unrelated families. A Portuguese boy was shown to carry a hemizygous missense mutation c.293T>C (p.L98S) in exon 3.The mutation was absent in the parents and the two brothers. In contrast, the neighboring polymorphism c.268C>G was transmitted by the heterozygous mother to all sons. Together, this suggested that p.L98S, which is evolutionary conserved between vertebrates and invertebrates, is a de novo mutation. Another hemizygous missense mutation, c.212G>A (p.R71H), was found in the same exon in two individuals of a German family. Both mutations were absent from more than 60,000 control individuals in the ExAC server. Functional studies using cell culture, Drosophila, and mouse models suggest that the missense mutations reduce the interaction with V0 assembly factors and, consequently, V-ATPase activity.Created: 13 Aug 2018, 3:20 p.m.
Comment on phenotypes: added disease from Gene2Phenotype and Orphanet : X-linked intellectual disability, Hedera type is a rare X-linked intellectual disability syndrome characterized by an onset in infancy of delayed motor and speech milestones, generalized tonic-clonic seizures and drop attacks, and mild to moderate intellectual disability. Additional, less common manifestations include scoliosis, ataxia (resulting in progressive gait disturbance), and bilateral pes planovalgus. Physical appearance is normal with no dysmorphic features reported.Created: 13 Aug 2018, 3:19 p.m.
Please note additional recent publication with functional evidence on more variants.Created: 14 Jun 2018, 9:35 a.m.
Mode of inheritance
X-LINKED: hemizygous mutation in males, biallelic mutations in females
Publications
Variants in this GENE are reported as part of current diagnostic practice
Associated with phenotype in OMIM and as a possible G2P. At least 2 variants reported, (c.321C>T, p.D107D) affects normal splicing (PMID 15746149) and c.168+6T-A predicted to affect splicing (PMID 26467484)Created: 15 Dec 2017, 9:38 a.m.
Mode of inheritance
X-LINKED: hemizygous mutation in males, biallelic mutations in females
Publications
Mode of inheritance
X-LINKED: hemizygous mutation in males, biallelic mutations in females
Phenotypes
MENTAL RETARDATION X-LINKED WITH EPILEPSY (MRXE)
Publications
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_2_4_2017;in_omim_20150205_movement . Main mutation mechanism : UncertainCreated: 27 Jul 2017, 5:08 p.m.
Evidences key, gene present in following gene lists and main mutation mechanism : ddg2p_20141118; gilissen_2014_candidate; omim_20150205_movement; Nijmegen_ID_diagnostic; Nijmegen_ID_candidates; GEL_ID_red_20160217; neuro_20160418_strict; Uncertain. 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 TrustCreated: 19 Jul 2017, 12:02 p.m.
Mode of inheritance
X-LINKED: hemizygous mutation in males, biallelic mutations in females
Publications
Source Victorian Clinical Genetics Services was added to ATP6AP2.
Gene: atp6ap2 has been classified as Green List (High Evidence).
Publications for gene: ATP6AP2 were set to 26467484; 15746149; 29127204; 25529582; 11782983
Phenotypes for gene: ATP6AP2 were set to Mental retardation, X-linked, syndromic, Hedera type, 300423; MENTAL RETARDATION X-LINKED WITH EPILEPSY; X-linked intellectual disability, Hedera type
Publications for gene: ATP6AP2 were set to 26467484; 15746149; 29127204; 25529582
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.
Expert Review Amber was added to ATP6AP2. Panel: Intellectual disability Publications for gene ATP6AP2 was set to ['26467484', ' 15746149', ' ']
The Gel status was updated for this whole panel
The Gel status was updated for this whole panel
ATP6AP2 was added to Intellectual disabilitypanel. Source: Expert Review Red Model of inheritance for gene ATP6AP2 was set to X-LINKED: hemizygous mutation in males, biallelic mutations in females
Model of inheritance for gene ATP6AP2 was changed to X-LINKED: hemizygous mutation in males, may be caused by monoallelic mutations in females
ATP6AP2 was added to Intellectual disabilitypanel. Sources: Emory Genetics Laboratory,Radboud University Medical Center, Nijmegen
ATP6AP2 was added to Intellectual disabilitypanel. Sources: Emory Genetics Laboratory,Radboud University Medical Center, Nijmegen