Intellectual disability - microarray and sequencing
Gene: PTRHD1The rating of this gene has been updated following NHS Genomic Medicine Service approval.Created: 9 Mar 2022, 3:40 p.m. | Last Modified: 9 Mar 2022, 3:40 p.m.
Panel Version: 3.1510
Comment on phenotypes: Gene-checked tag removed as this gene now has a relevant phenotype listed in OMIM (Neurodevelopmental disorder with early-onset parkinsonism and behavioral abnormalities, OMIM:620747)Created: 3 Apr 2024, 11:15 a.m. | Last Modified: 3 Apr 2024, 11:15 a.m.
Panel Version: 5.514
Comment on list classification: Changed rating from Green to Amber so that Green genes on this panel reflect the NHS signed-off version. This will be reviewed at the next GMS panel update (added 'for-review' tag).Created: 20 Oct 2020, 2:45 p.m. | Last Modified: 20 Oct 2020, 2:45 p.m.
Panel Version: 3.472
Comment when marking as ready: Further case from personal correspondence. Considered sufficient for a green rating.Created: 15 May 2020, 4:11 p.m. | Last Modified: 15 May 2020, 4:11 p.m.
Panel Version: 3.65
Personal correspondence about a new diagnosis from within the 100,000 genomes project data. A child presenting with learning difficulties, autism, shuffling gait, calf wasting and normal CK has been detected as having homozygous LOF variants in PTRHD1. Reported as class V via NHS diagnostic lab. In view of this additional case and phenotypic overlap (Intellectual disability and Parkinsonian features), I am promoting this gene to green.Created: 15 May 2020, 4:08 p.m. | Last Modified: 15 May 2020, 4:08 p.m.
Panel Version: 3.62
Mode of inheritance
BIALLELIC, autosomal or pseudoautosomal
Comment on list classification: Konstantinos Varvagiannis submitted an Amber review for PTRHD1. OMIM has rated this as VUS (last update : 02/23/2017) based on papers (PMID: 27134041, 27753167) involving two separate variants from two Iranian families. Kuipers et al. (PMID: 30398675) report on 3 individuals of African origin with identical phenotype with a homozygous for a frameshift PTRHD1 deletion. Limited information provided on ID therefore adding to watchlist and rating as AmberCreated: 30 May 2019, 9:15 a.m.
7 individuals with biallelic PTRHD1 mutations from 3 pedigrees have been reported. The phenotype in all consisted of early-onset Parkinsonism with intellectual disability (overview in Table 1 - PMID: 30398675).
Jaberi et al. (PMID: 27134041) first reported on 2 sibs born to consanguineous Iranian parents. Both presented with parkinsonism with ID. After homozygosity mapping and exome sequencing, one variant in PTRHD1 (NM_001013663.1:c.155G>A or p.Cys52Tyr) as well as another variant in ADORA1 were the only candidates for the patients phenotype. At the time, the authors favored ADORA1 as the causative gene for their patients' phenotype but could not exclude pathogenicity of PTRHD1.
Khodadadi et al. (PMID: 27753167) published on 2 additional sibs from Iran with a similar phenotype. These individuals - born to consanguineous parents - were homozygous for a further PTRHD1 missense variant (p.His53Tyr) which is proximal to the variant reported by Jaberi et al.
This led the authors of the first publication to acknowledge that PTRHD1 was probably responsible for their patients' phenotype (PMID: 29143421). [A recent study of exome sequencing data of a Parkinson disease 1214-patient cohort failed to find any case explained by biallelic ADORA1 mutations - PMID: 27987235].
The variants reported in these 2 publications are classified as VUS in OMIM (last update : 02/23/2017).
Kuipers et al. (PMID: 30398675) report on 3 additional individuals of African origin with identical phenotype. These individuals, whose parents originated from an isolated african community, were homozygous for a frameshift PTRHD1 deletion (c.169_196del or p.Ala57Argfs*26). This variant is rare in gnomAD (MAF of 0.018% overall or 0.15% in the African subpopulation). Alternative causes of PD / parkinsonism were previously excluded.
The phenotype of all reported individuals is summarized in Table 1 of this article.
PTRHD1 is not assocated with any phenotype in OMIM nor in G2P.
This gene is included in the gene panel for ID, offered by Radboudumc.
Therefore, this gene can be considered for inclusion in this panel as amber or green.
[Please consider inclusion of this gene in the Parkinson Disease and Complex Parkinsonism gene panel].
Sources: Literature, Radboud University Medical Center, NijmegenCreated: 12 Dec 2018, 2:24 p.m.
Mode of inheritance
BIALLELIC, autosomal or pseudoautosomal
Phenotypes
Parkinsonism; Intellectual disability
Publications
Variants in this GENE are reported as part of current diagnostic practice
Phenotypes for gene: PTRHD1 were changed from Intellectual disability; Parkinsonism to Neurodevelopmental disorder with early-onset parkinsonism and behavioral abnormalities, OMIM:620747
Tag gene-checked was removed from gene: PTRHD1.
Tag gene-checked tag was added to gene: PTRHD1.
Tag for-review was removed from gene: PTRHD1.
Source Expert Review Green was added to PTRHD1. Rating Changed from Amber List (moderate evidence) to Green List (high evidence)
Gene: ptrhd1 has been classified as Amber List (Moderate Evidence).
Tag for-review tag was added to gene: PTRHD1.
Gene: ptrhd1 has been classified as Green List (High Evidence).
Phenotypes for gene: PTRHD1 were changed from Intellectual disability; Parkinsonism, Intellectual disability; Parkinsonism to Intellectual disability; Parkinsonism
Gene: ptrhd1 has been classified as Green List (High Evidence).
Tag watchlist was removed from gene: PTRHD1.
Gene: ptrhd1 has been classified as Green List (High Evidence).
Gene: ptrhd1 has been classified as Green List (High Evidence).
Tag watchlist tag was added to gene: PTRHD1.
Source Expert Review was added to PTRHD1. Source Expert Review Amber was added to PTRHD1. Added phenotypes Parkinsonism, Intellectual disability for gene: PTRHD1 Publications for gene PTRHD1 were changed from 30398675; 27134041; 29143421; 27753167 to 30398675; 27134041; 27753167; 29143421 Rating Changed from No List (delete) to Amber List (moderate evidence)
gene: PTRHD1 was added gene: PTRHD1 was added to Intellectual disability. Sources: Literature,Radboud University Medical Center, Nijmegen Mode of inheritance for gene: PTRHD1 was set to BIALLELIC, autosomal or pseudoautosomal Publications for gene: PTRHD1 were set to 30398675; 27134041; 29143421; 27753167 Phenotypes for gene: PTRHD1 were set to Parkinsonism; Intellectual disability Penetrance for gene: PTRHD1 were set to Complete Review for gene: PTRHD1 was set to AMBER gene: PTRHD1 was marked as current diagnostic