Fetal anomalies
Gene: HAND2 Amber List (moderate evidence)I don't know
No OMIM gene disease association. Borderline red-amber gene.
PMID: 26676105 Lu et al 2016 - 145 unrelated patients with CHD, Han Chinese descent versus 200 unrelated controls had HAND2 gene sequencing. In x1 patient with ToF hetrozygous HAND2 c.140T>C p.L47P variant identified, parents unaffected, variant reported to be de novo but paternity not confirmed. Absent from gnomad, x1 het synonymous variant in this position only. Functional analysis showed reduced transcriptional activity
PMID: 32134193 Cohen et al 2020 - 31-month-old male with unicommissural unicuspid aortic valve, moderate aortic stenosis, and mild pulmonic stenosis. CMA identified 546kb deletion on chr 4q34.1 (174364195-174910239[GRCh37/hg19]). Deletion encompasses exons 1 and 2 of SCRG1, HAND2, and HAND2-AS1. Deletion paternally inherited - proband's father had history of ToF. Novel deletion - no similar deletions in Decipher or DGV. Proband also had CHD7 VUS (c.2830C>T, p.Arg944Cys) – but no features of CHARGE syndrome and CHD7 variant present in 7 hets in gnomad
PMID: 30217752 Liu et al 2019 - screened 206 unrelated Han Chinese patients with adult-onset idiopathic DCM and 300 unrelated controls. Identified HAND2 variant c.199G>T; p.(Glu67*). Authors report segregation of the variant with other affected individuals in the family including x2 with VSD/PDA
PMID: 26865696 Sun et al 2016 - HAND2 sequenced in 192 unrelated Han Chinese patient. Het p.S65I variant identified in a patient with VSD and present in all 7 family members with CHD and absent from 13 unaffected members.
Variant present in gnomad – 3 hets (x1 East Asian, x1 South Asian, x1 Latin American)
PMID 20819618 - Shen et al 2010 131 unrelated Han Chinese patients with ToF had HAND2 gene sequencing. Het c.32C>G p.Pro11Arg identified in x2 unrelated patients – no seg, not in gnomad but in area of low coverage.
c.42C>T – present in x1 patient with ToF + VSD – no segregation data, not in gnomad but in area of low coverageCreated: 20 Jan 2022, 10:47 a.m. | Last Modified: 20 Jan 2022, 10:47 a.m.
Panel Version: 0.2597
Heterozygous LoF variants associated with congenital heart defects reported in at least 3 unrelated families.
Sources: Literature, Expert listCreated: 20 Dec 2021, 1:19 a.m.
Mode of inheritance
MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Phenotypes
Congenital heart defects
Publications
Phenotypes for gene: HAND2 were changed from Congenital heart defects to Congenital heart disease, MONDO:0005453, HAND2-related
Gene: hand2 has been classified as Amber List (Moderate Evidence).
Gene: hand2 has been classified as Amber List (Moderate Evidence).
gene: HAND2 was added gene: HAND2 was added to Fetal anomalies. Sources: Literature,Expert list Mode of inheritance for gene: HAND2 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted Publications for gene: HAND2 were set to 26865696; 32134193; 26676105 Phenotypes for gene: HAND2 were set to Congenital heart defects Review for gene: HAND2 was set to GREEN
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 panelapp@genomicsengland.co.uk
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.