CRKL – Congenital Heart Disease

Congenital heart disease (CHD) comprises structural cardiac malformations, with conotruncal defects accounting for ~20% of cases. CRKL (HGNC:2363) encodes an SH2/SH3 adaptor protein located within the 22q11.2 locus and has been implicated in outflow tract development. Rare copy number variants (CNVs) involving CRKL have been identified in infants and adults with tetralogy of Fallot (HP:0001636) and other CHDs, suggesting gene dosage sensitivity. This summary evaluates genetic and functional evidence supporting CRKL haploinsufficiency in non-syndromic CHD, offering guidance for diagnostic testing and research priorities.

In a cohort of 389 California infants with tetralogy of Fallot or d-transposition of the great arteries, array comparative genomic hybridization detected eight high-priority microdeletions and duplications implicating CRKL among five candidate genes (PMID:24127225). These findings established CRKL as a dosage-sensitive gene in conotruncal development.

An adult CHD screening study of 100 Han Chinese patients identified 45 rare CNVs in 36 individuals, including a 22q11.2 microdeletion encompassing CRKL (PMID:24115576). This observation extended the implication of CRKL CNVs beyond pediatric cases to adult survivors of simple-to-moderate CHD without syndromic features.

In South African patients with non-syndromic CHD, high-resolution microarray analysis of 90 individuals revealed eight CNVs in known CHD genes, including one overlapping CRKL (PMID:36205932). The CRKL CNV occurred in one patient (1.1%), confirming its presence across diverse ancestries.

Inheritance is consistent with autosomal dominant haploinsufficiency. To date, three unrelated probands carry heterozygous CRKL copy number gains or losses, without evidence of familial segregation. Variant classes are restricted to CNVs; no point mutations in CRKL have been reported in isolated CTD cohorts. Recurrent variants or founder alleles have not been observed.

Functional data specific to CRKL dosage in cardiac development are limited. Dosage sensitivity is inferred from CNV studies and the established role of CRKL in intracellular signaling, yet no targeted in vivo or in vitro cardiac assays of CRKL haploinsufficiency have been reported.

Collectively, the current evidence supports a limited clinical validity for CRKL in non-syndromic CHD based on rare CNVs across independent cohorts. Additional segregation studies and functional modeling in cardiac tissues are needed to reach higher classification. Key take-home: CRKL haploinsufficiency should be considered in CNV testing panels for conotruncal heart defects.

References

• American journal of medical genetics. Part A • 2014 • Identification of novel candidate gene loci and increased sex chromosome aneuploidy among infants with conotruncal heart defects. PMID:24127225
• American journal of medical genetics. Part A • 2013 • High-resolution analysis of copy number variants in adults with simple-to-moderate congenital heart disease. PMID:24115576
• Circulation. Genomic and precision medicine • 2022 • Investigation of Copy Number Variation in South African Patients With Congenital Heart Defects. PMID:36205932

Evidence Based Scoring (AI generated)