Intellectual disability - microarray and sequencing
Gene: HNRNPK Green List (high evidence)Green List (high evidence)
Please also note high number of likely pathogenic and pathogenic variants reported in this gene by clinical laboratories in ClinVarCreated: 18 Jun 2018, 1:52 p.m.
Mode of inheritance
MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Variants in this GENE are reported as part of current diagnostic practice
Green List (high evidence)
Comment on list classification: Changed from Amber to Green, there is now enough evidence to support gene-disease association.Created: 9 Aug 2018, 12:09 p.m.
in view of external clinical review this gene was reviewed again. The pathogenic variants listed in ClinVar were submitted by Clinical Genetics Research Group, University of Calgary and relates to the recently published paper by Au PYB et al,. (2018) PMID: 29904177 who reported 6 additional cases with Au-Kline syndrome (AKS). These additional patients also demonstrated that AKS does have a distinct facial gestalt and phenotype that can be differentiated from Kabuki syndrome (KS).Kline syndrome (AKS, OMIM 616580) is a multiple malformation syndrome, first reported in 2015, associated with intellectual disability. There are now a total of 9 patients with de novo loss-of-function variants in HNRNPK, one individual with a de novo missense variant in addition to 3 patients with de novo deletions of 9q21.32 that encompass HNRNPK.Created: 9 Aug 2018, 12:06 p.m.
Comment on publications: Added recent publication to support green rating. Au PYB et al,. (2018) PMID: 29904177 reported 6 additional cases with Au-Kline syndromeCreated: 9 Aug 2018, 11:38 a.m.
Comment on mode of inheritance: updated MOI as suggested by expert review and publicationCreated: 9 Aug 2018, 11:31 a.m.
After review with the clinical team about the clinical overlap with Au-Kline syndrome and Kabuki syndrome it was decided not to add this gene to the Kabuki syndrome panel. Only with further cases we will get a better idea of the phenotypic spectrum aside from ID.Created: 18 Dec 2017, 4:23 p.m.
HNRNPK haploinsufficiency causes Au-Kline syndrome which presents with psychomotor developmental delay, intellectual disability, characteristic face, cardiac, urogenital, skeletal abnormalities, and hypotonia. To date only two unrelated cases have been reported. Also it is thought there is clinical overlap with Kabuki syndrome PMID: 26954065,28771707,28374925.Created: 18 Dec 2017, 3:36 p.m.
Mode of inheritance
MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Phenotypes
Au-Kline syndrome, 616580
Publications
Comment on list classification: This gene was sourced from the ClinGen Gene Validity Classification Summary. Determined as MODERATE by calculated classification and MODERATE by Expert curation (dated 11/15/2016). Available here: https://search.clinicalgenome.org/kb/gene-validity/5456. Comments provided by the expert curation: Evidence is rapidly emerging supporting the association between HNRNPK and Au-Kline syndrome. Gallardo et al. published a paper in 2015 describing an Hnrnpk +/- haploinsufficient mouse, which they developed to study its role in tumorigenesis. Personal communication with the senior author of that paper, Sean Post, in August 2016, revealed that the haploinsufficient mice appeared to have "significant reduction in overall size and had numerous structural/bone abnormalities," remniscient of the human phenotype, though he clarified that his group is not able to formally assess them for these types of phenotypes. Additionally, we are aware of at least one additional unpublished case - this evidence is not being formally considered, as it is not part of the public domain.Created: 4 Jul 2017, 2:39 p.m.
Mode of inheritance
MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Phenotypes
Neurodevelopmental disorder-craniofacial dysmorphism-cardiac defect-hip dysplasia syndrome due to a point mutation; OMIM:616580; Orphanet:453499
Publications
Source Victorian Clinical Genetics Services was added to HNRNPK.
Gene: hnrnpk has been classified as Green List (High Evidence).
Publications for gene: HNRNPK were set to 26173930; 26954065; 28771707; 26638989; 28374925; 29904177
Mode of inheritance for gene: HNRNPK was changed from MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: HNRNPK were set to 26173930; 26954065; 28771707; 26638989; 28374925
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.
Publications for HNRNPK were set to 26173930; 26954065; 28771707; 26638989
Model of inheritance for gene HNRNPK was set to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown Publications for gene HNRNPK was set to ['26173930', ' 26954065', '28771707 ']
This gene has been classified as Amber List (Moderate Evidence).
This gene has been classified as Amber List (Moderate Evidence).
HNRNPK was added to Intellectual disabilitypanel. Sources: Other
HNRNPK was created by ellenmcdonagh
If promoting or demoting a gene, please provide comments to justify a decision to move it.
Genes included in a Genomics England gene panel for a rare disease category (green list) should fit the criteria A-E outlined below.
These guidelines were developed as a combination of the ClinGen DEFINITIVE evidence for a causal role of the gene in the disease(a), and the Developmental Disorder Genotype-Phenotype (DDG2P) CONFIRMED DD Gene evidence level(b) (please see the original references provided below for full details). These help provide a guideline for expert reviewers when assessing whether a gene should be on the green or the red list of a panel.
A. There are plausible disease-causing mutations(i) within, affecting or encompassing an interpretable functional region(ii) of this gene identified in multiple (>3) unrelated cases/families with the phenotype(iii).
OR
B. There are plausible disease-causing mutations(i) within, affecting or encompassing cis-regulatory elements convincingly affecting the expression of a single gene identified in multiple (>3) unrelated cases/families with the phenotype(iii).
OR
C. As definitions A or B but in 2 or 3 unrelated cases/families with the phenotype, with the addition of convincing bioinformatic or functional evidence of causation e.g. known inborn error of metabolism with mutation in orthologous gene which is known to have the relevant deficient enzymatic activity in other species; existence of an animal model which recapitulates the human phenotype.
AND
D. Evidence indicates that disease-causing mutations follow a Mendelian pattern of causation appropriate for reporting in a diagnostic setting(iv).
AND
E. No convincing evidence exists or has emerged that contradicts the role of the gene in the specified phenotype.
(i)Plausible disease-causing mutations: Recurrent de novo mutations convincingly affecting gene function. Rare, fully-penetrant mutations - relevant genotype never, or very rarely, seen in controls. (ii) Interpretable functional region: ORF in protein coding genes miRNA stem or loop. (iii) Phenotype: the rare disease category, as described in the eligibility statement. (iv) Intermediate penetrance genes should not be included.
It’s assumed that loss-of-function variants in this gene can cause the disease/phenotype unless an exception to this rule is known. We would like to collect information regarding exceptions. An example exception is the PCSK9 gene, where loss-of-function variants are not relevant for a hypercholesterolemia phenotype as they are associated with increased LDL-cholesterol uptake via LDLR (PMID: 25911073).
If a curated set of known-pathogenic variants is available for this gene-phenotype, please contact us at [email protected]
We classify loss-of-function variants as those with the following Sequence Ontology (SO) terms:
Term descriptions can be found on the PanelApp homepage and Ensembl.
If you are submitting this evaluation on behalf of a clinical laboratory please indicate whether you report variants in this gene as part of your current diagnostic practice by checking the box
Standardised terms were used to represent the gene-disease mode of inheritance, and were mapped to commonly used terms from the different sources. Below each of the terms is described, along with the equivalent commonly-used terms.
A variant on one allele of this gene can cause the disease, and imprinting has not been implicated.
A variant on the paternally-inherited allele of this gene can cause the disease, if the alternate allele is imprinted (function muted).
A variant on the maternally-inherited allele of this gene can cause the disease, if the alternate allele is imprinted (function muted).
A variant on one allele of this gene can cause the disease. This is the default used for autosomal dominant mode of inheritance where no knowledge of the imprinting status of the gene required to cause the disease is known. Mapped to the following commonly used terms from different sources: autosomal dominant, dominant, AD, DOMINANT.
A variant on both alleles of this gene is required to cause the disease. Mapped to the following commonly used terms from different sources: autosomal recessive, recessive, AR, RECESSIVE.
The disease can be caused by a variant on one or both alleles of this gene. Mapped to the following commonly used terms from different sources: autosomal recessive or autosomal dominant, recessive or dominant, AR/AD, AD/AR, DOMINANT/RECESSIVE, RECESSIVE/DOMINANT.
A variant on one allele of this gene can cause the disease, however a variant on both alleles of this gene can result in a more severe form of the disease/phenotype.
A variant in this gene can cause the disease in males as they have one X-chromosome allele, whereas a variant on both X-chromosome alleles is required to cause the disease in females. Mapped to the following commonly used term from different sources: X-linked recessive.
A variant in this gene can cause the disease in males as they have one X-chromosome allele. A variant on one allele of this gene may also cause the disease in females, though the disease/phenotype may be less severe and may have a later-onset than is seen in males. X-linked inactivation and mosaicism in different tissues complicate whether a female presents with the disease, and can change over their lifetime. This term is the default setting used for X-linked genes, where it is not known definitately whether females require a variant on each allele of this gene in order to be affected. Mapped to the following commonly used terms from different sources: X-linked dominant, x-linked, X-LINKED, X-linked.
The gene is in the mitochondrial genome and variants within this can cause this disease, maternally inherited. Mapped to the following commonly used term from different sources: Mitochondrial.
Mapped to the following commonly used terms from different sources: Unknown, NA, information not provided.
For example, if the mode of inheritance is digenic, please indicate this in the comments and which other gene is involved.