Cardiomyopathy_Paediatric

Gene: ABCC9

Green List (high evidence)

Cardiomegaly and cardiac hypertrophy are features of Cantu syndrome.

Concerns regarding association with isolated DCM noted.

Created: 3 Nov 2023, 6:33 a.m. | Last Modified: 3 Nov 2023, 6:33 a.m.

Panel Version: 0.170

Mode of inheritance
MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted

Phenotypes
Hypertrichotic osteochondrodysplasia (Cantu syndrome), MIM# 239850

I don't know

Reviewed in July 2023:

- Gene is well-established for:
Hypertrichotic osteochondrodysplasia (Cantu syndrome), AD - GoF
Intellectual disability and myopathy syndrome, AR - previously known as ABCC9-related Intellectual disability Myopathy Syndrome (AIMS) - LoF

- The association of NMD-pred ABCC9 variants with AD non-syndromic cardiac conditions (DCM/AF) is not well established. These variants have been reported in DCM patients and also in unaffected individuals, and with conflicting classifications: VUS (majority), likely pathogenic, and pathogenic. See gnomAD, ClinVar, PMID:27532257, PMID:28991257, PMID:36129056.

ClinGen: LIMITED for AD dilated cardiomyopathy (11/13/2020).

gnomADv2: pLI=0, many NMD-predicted variants listed.

PMID: 27532257: 1x DCM with Q57X
PMID: 28991257: 1x proband with conotruncal defects p.Q57X. In addition, heterozygous Q57X, S454X, G1090fs in individuals not known to be affected (parents of this congenital heart disease cohort).
PMID: 36129056: 4x NMD-pred variants in 4 unrelated probands from an exome sequencing cohort, no patient-specific phenotypic info provided, patients referred for diagnostic ES for any indication (including DCM).

PMID: 15034580 ref in OMIM for AD DCM: this variant is not NMD-pred, and is located in only one of the 4 RefSeq transcripts (not in the MANE transcript). It has been classified as VUS by many clinical testing laboratories (ClinVar VCV000222477.28).

PMID: 31575858: Homozygous canonical splice site variant reported in two fams with 6 pts with ABCC9-related Intellectual disability Myopathy Syndrome (AIMS), cardiac systolic dysfunction found in two oldest patients, all have cerebral white matter hyperintensities. Parents were heterozygous and unaffected. cDNA studies using RNA from patient fibroblasts showed variant results in an inframe del of exon 8.

Created: 25 Oct 2023, 6:25 a.m. | Last Modified: 25 Oct 2023, 6:25 a.m.

Panel Version: 0.170

Mode of inheritance
BOTH monoallelic and biallelic, autosomal or pseudoautosomal

Phenotypes
Hypertrichotic osteochondrodysplasia (Cantu syndrome) (MIM#239850), AD; Intellectual disability and myopathy syndrome (MIM#619719), AR; Cardiomyopathy, dilated, 1O (MIM#608569), AD

Publications

• 27532257
• 28991257
• 36129056
• 31575858
• 15034580

Variants in this GENE are reported as part of current diagnostic practice