Congenital Heart Defect

Gene: HAND2

I don't know

Single additional relevant report detailing associations between HAND2 variants and cardiac defects published since previous review (Jan 2022). No segregation analysis, de novo mutation is large deletion encompassing 3 genes:
PMID: 36427970 Chen et al 2022. Prenatal detection of de novo 17.8Mb deletion of 4q34.1→qter including HAND2, SORBS2 and DUX4. Associated with low pregnancy associated plasma protein-A (PAPP-A) and low placental growth factor (PlGF) in the first-trimester maternal serum screening, congenital heart defect (CHD) on fetal ultrasound and a false negative non-invasive prenatal testing (NIPT) result.

No pathogenic variants listed in Clinvar apart from p.(Glu67*) - see previously reviewed PMID:30217752.

Insufficient additional evidence to change gene rating from Amber.

Created: 22 Oct 2023, 10:22 p.m. | Last Modified: 23 Oct 2023, 3:42 a.m.

Panel Version: 0.295

Mode of inheritance
MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted

Phenotypes
Congenital heart disease

Publications

• PMID: 36427970

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 coverage

Created: 20 Jan 2022, 10:49 a.m. | Last Modified: 20 Jan 2022, 10:49 a.m.

Panel Version: 0.170

Mode of inheritance
MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted

Phenotypes
Congenital heart disease

Publications

• 26865696
• 32134193
• 26676105
• 30217752
• 20819618