Intellectual disability - microarray and sequencing
Gene: PHF21AComment on phenotypes: Potocki-Shaffer syndrome (MIM:601224) is a contiguous gene deletion syndrome involving genes on chromosome 11p11.2.Created: 11 May 2020, 12:53 p.m. | Last Modified: 11 May 2020, 12:53 p.m.
Panel Version: 3.45
Potocki-Shaffer syndrome thought to caused by a deletion of 11p11.2, the minimum deleted region contains at least five genes, including PHF21A.
Hamanaka et al in PMID: 30487643 reported on three individuals who all underwent trio WES to have de novo, variants in PHF21A. All individuals had DD and ID although mild in one case. This is the first reporting of LOF variants solely in PHF21A.
PHF21A is not currently associated with any phenotypes in OMIM but is classed probable and associated with Disease: POTOCKI-SHAFFER SYNDROME in Gene2Phenotype.
Combined with the functional evidence and two expert reviews, there is now enough evidence for PHF21A to be classed as Green.Created: 29 Jul 2019, 2:16 p.m. | Last Modified: 29 Jul 2019, 2:18 p.m.
Panel Version: 2.990
Hamanaka et al recently used WES to identify 3 individuals with ID/craniofacial anomalies harbouring de novo, presumed loss of function variants in PHF21A (PMID: 30487643). As well as ID/CFA, it is suggested that variable features may also include epilepsy, autism spectrum disorder and overgrowth. This study adds to the previous evidence supporting a role for haploinsufficiency of this gene being responsible for the ID/CFA phenotypes associated with 11p11.2 deletion syndrome (Potocki-Shaffer syndrome) such that a green rating now seems appropriate.
Previous evidence includes i) 3 cases with balanced translocations disrupting PHF21A (PMID: 22770980; 27124303) and ii) several comparison studies looking at the phenotypes in patients with 11p11.2 deletions of different lengths (e.g. PMID: 28127865; 26333423).
There is a further case listed in ClinVar (SCV000741718.1) with p.Arg390Ter in individual with CFA and ID/DD and we are aware of further unpublished cases.Created: 13 Feb 2019, 10:33 a.m.
Mode of inheritance
MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Phenotypes
intellectual disability; craniofacial anomalies; epilepsy; ASD; overgrowth
Publications
Several lines of evidence suggest that haploinsufficiency of PHF21A is responsible for the intellectual disability (ID) as well as some of the craniofacial anomalies (CFA) observed in Potocki-Shaffer syndrome (11p11.2 deletion syndrome - PSS / MIM 601224).
PMID: 22770980 reports on 3 individuals with reciprocal translocations involving 11p11.2, all shown to disrupt PHF21A. All patients presented with ID and facial features similar to those observed in PSS.
In two instances, sequencing of the breakpoints was suggestive of a fusion product (PHF21A/ELAVL1 and PHF21A/ARHGAP6) while in one case the translocation led to simple truncation of PHF21A, as the breakpoint in the other chromosome involved in the translocation mapped to a gene desert.
Sequencing of the PHF21A allele on the nontranslocated chromosome did not demonstrate the presence of additional variants.
PHF21A lies within a 1.1 Mb critical interval for the phenotypes of ID and CFA in PSS.
Functional studies in mice and zebrafish support a role in CNS as well as in the development of CFA. PHF21A, together with LSD1 participate in a complex important for the repression of neuron-specific genes as demonstrated for the case of KCN3A in patient lymphoblasts.
PMID: 30487643 reports on 3 unrelated individuals with de novo truncating PHF21A variants. ID as well as CFA were noted in all, while - as expected - other features of PSS such as exostoses and parietal foramina (explained by haploinsufficiency of EXT2 and ALX4 respectively in the case of 11p deletions) were absent.
3 different loss-of-function variants are reported, one of which was located in the penultimate exon of the gene (using NM_001101802.1 as a reference).
PHF21A is included in gene panels for intellectual disability offered by diagnostic laboratories and few SNVs have been submitted in ClinVar [ https://www.ncbi.nlm.nih.gov/clinvar/?term=PHF21A - eg. variation 521226 ].
As a result, this gene can be considered for upgrade to green.Created: 2 Dec 2018, 3:56 p.m.
Mode of inheritance
MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Publications
Variants in this GENE are reported as part of current diagnostic practice
Probable gene in Developmental Disorders Genotype-Phenotype Database (DDG2P) associated to Potocki-Shaffer syndrome (PSS) which is characterized by multiple exostoses, parietal foramina, enlargement of the anterior fontanelle and occasionally intellectual deficit and mild cranio-facial anomalies. To date, 23 individuals from 14 families have been reported. The syndrome is caused by contiguous gene deletions on the short arm of chromosome 11 (11p11.2). Summary by McCoool (2017) PMID: 28127865 denoted that the literature implicates haploinsufficiency of three genes (ALX4, EXT2, and PHF21A) in causing some of the cardinal features of PSS. Deletion of EXT2 (OMIM 608210) causes the characteristic exostoses, and deletion of ALX4 (OMIM 605420) has been shown to cause parietal foramina (PMID:9489802, 11017806, 11903336, 15852040). More recently, reports have implicated haploinsufficiency of PHF21A (OMIM 608325) as the cause for the abnormal craniofacial features and intellectual disability typical of PSS (PMID:22770980,26333423).Created: 18 Dec 2017, 3:39 p.m.
Mode of inheritance
MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Phenotypes
Potocki-Shaffer syndrome, 601224; Intellectual disability
Publications
Mode of inheritance
MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Phenotypes
POTOCKI-SHAFFER SYNDROME
Publications
Comment on list classification: Candidate in Potocki-Shaffer deletion regionCreated: 7 Feb 2016, 11:55 p.m.
Phenotypes for gene: PHF21A were changed from Potocki-Shaffer syndrome, 601224; PSS; Intellectual disability; Intellectual developmental disorder with behavioral abnormalities and craniofacial dysmorphism with or without seizures, 618725 to Potocki-Shaffer syndrome, 601224; PSS; Intellectual disability; Intellectual developmental disorder with behavioral abnormalities and craniofacial dysmorphism with or without seizures, 618725
Phenotypes for gene: PHF21A were changed from Potocki-Shaffer syndrome, 601224; PSS; Intellectual disability to Potocki-Shaffer syndrome, 601224; PSS; Intellectual disability; Intellectual developmental disorder with behavioral abnormalities and craniofacial dysmorphism with or without seizures, 618725
Gene: phf21a has been classified as Green List (High Evidence).
Publications for gene: PHF21A were set to 22770980; 26333423; 8456828; 8882796; 14872200; 9489802; 11017806; 11903336; 15852040; 23239541; 28127865
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 PHF21A. Panel: Intellectual disability Model of inheritance for gene PHF21A was set to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown Publications for gene PHF21A was set to ['22770980', '26333423', '8456828', '8882796', '14872200', '9489802', '11017806', '11903336', ' 15852040', ' 23239541', '28127865']
This gene has been classified as Red List (Low Evidence).
This gene has been classified as Red List (Low Evidence).
The Gel status was updated for this whole panel
The Gel status was updated for this whole panel
PHF21A was added to Intellectual disabilitypanel. Sources: Expert Review Amber
PHF21A was created by ellenmcdonagh