Intellectual disability - microarray and sequencing
Gene: KIF2A Green List (high evidence)Three further cases identified in the literature.
PMID:27747449 (Cavallin et al 2017) detected two de novo p.Ser317Asn and p.His321Pro mutations in KIF2A in two patients with lissencephaly and microcephaly. Case 1 had DD, no epilepsy but was only 9 months old at last reporting. Case 2 had neonatal seizures and severe DD.
PMID:27896282 (Tian et al 2016) report a patient with lissencephaly, developmental delay, and infantile spasms, due to de novo heterozygous variant in KIF2A (p.Thr320Ile).
Most cases identified have epilepsy first however as one individual did not have seizures KIF2A is relevant for the ID panel.
Therefore upgrading rating from Amber to Green as now sufficient (>3) unrelated cases.Created: 24 Jul 2019, 10:38 a.m. | Last Modified: 25 Jul 2019, 8:29 a.m.
Panel Version: 2.977
Green List (high evidence)
Further to the articles that have been cited previously, 3 additional individuals with KIF2A de novo variants and a similar phenotype have been reported:
PMID 27747449 reports on a 9 month-old female with congenital microcephaly and posteriorly predominant lissencephaly, with a de novo missense variant (p.Ser317Asn) in KIF2A. A second patient with lissencephaly of the same type and severe ID is described. This individual was found to have a de novo missense variant in KIF2A (p.His321Pro). The authors have excluded alternative causes (gene panel analysis and prior aCGH performed for both patients). p.Ser317 and p.His321 are proposed as hotspots since the first variant (Ser317Asn) was previously described, while His321Pro concerns the same AA as in a previously described individual (His321Asp) [both in PMID 23603762].
PMID 27896282 reports on a 9 month-old female with lissencephaly and a de novo missense variant p.Thr320Ile. Expression studies were suggestive of a different pattern of cellular localization compared to wt and of abnormal microtubules.
This variant has also been submitted as likely pathogenic in ClinVar by a (seemingly) different submitter (Variation 435642).
[The variants in the different articles would correspond to the same AA positions whether NM_004520 or NM_001098511 is used as a reference sequence].Created: 13 Aug 2018, 12:23 p.m.
Mode of inheritance
MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Phenotypes
MALFORMATIONS OF CORTICAL DEVELOPMENT AND MICROCEPHALY
Publications
I don't know
Amber - two reports of different variants in this gene linked to severe developmental delay, amongst other phenotypes (PMID:23603762). There is a 5q12 deletion reported in the literature which encompasses this gene and eleven others - patients have been noted to express mental retardation(PMID:21594994)Created: 13 Dec 2017, 10:16 p.m.
Mode of inheritance
MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Publications
I don't know
Mode of inheritance
MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Phenotypes
MALFORMATIONS OF CORTICAL DEVELOPMENT AND MICROCEPHALY.
Publications
I don't know
Comment on list classification: 2 cases reported to date. Pending further data before diagnosticCreated: 7 Feb 2016, 9:35 p.m.
Gene: kif2a has been classified as Green List (High Evidence).
Phenotypes for gene: KIF2A were changed from Cortical dysplasia, complex, with other brain malformations 3, 615411 to Cortical dysplasia, complex, with other brain malformations 3, 615411
Phenotypes for gene: KIF2A were changed from Cortical dysplasia, complex, with other brain malformations 3, 615411 to Cortical dysplasia, complex, with other brain malformations 3, 615411
Phenotypes for gene: KIF2A were changed from MALFORMATIONS OF CORTICAL DEVELOPMENT AND MICROCEPHALY. to Cortical dysplasia, complex, with other brain malformations 3, 615411
Publications for gene: KIF2A were set to 23603762; 21594994; 27747449; 27896282
Publications for gene: KIF2A were set to 23603762; 21594994; 27747449; 27896282
Publications for gene: KIF2A were set to 23603762; 21594994
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 KIF2A. Panel: Intellectual disability Model of inheritance for gene KIF2A was set to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown Publications for gene KIF2A was set to ['23603762', ' 21594994']
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
KIF2A was created by ellenmcdonagh
KIF2A was added to Intellectual disabilitypanel. Sources: Expert Review Amber
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.