Dilated cardiomyopathy in a child with truncating mutation in NRAP gene

Ahmed, Hind Abdelrahman; Al-Ghamdi, Saleh; Mutairi, Fuad Al

doi:10.24911/jbcgenetics/183-1542267981

Cited by 3 publications

(3 citation statements)

References 21 publications

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“…Previous reports involving NRAP gene did not include segregation analysis [ 13 ] had insufficient data obtained from the family studies to fully support segregation or were inconsistent with co-segregation [ 12 , 14 , 15 ]. In the first study suggesting association of NRAP with cardiomyopathy, the proband’s 35-year-old brother who was homozygous for PTV in NRAP was considered unaffected while being asymptomatic and having normal echocardiography and ECG [ 12 ].…”

Section: Discussionmentioning

confidence: 99%

“…Thus, the authors concluded that NRAP may be a low penetrance genetic risk factor for DCM even though the previous observation can also be explained by age-dependent penetrance of cardiomyopathies. Later, Ahmed et al published a consanguineous pedigree in which the index patient was a baby girl who presented at the age of 13 months with heart failure, easy fatigability, weakness, irritability, and shortness of breath and was diagnosed with DCM [ 15 ]. Whole exome sequencing revealed that her healthy 33-year-old father was homozygous for the same frameshift variant identified in the proband whereas the mother was heterozygous.…”

Section: Discussionmentioning

confidence: 99%

“…Recently, biallelic protein-truncating variants (PTVs) in the nebulin-related anchoring protein gene (NRAP) have been identified in a few patients with severe sporadic DCM [12][13][14][15], and have been proposed to cause low-penetrant recessive DCM (Table 1). However, two healthy individuals (age 33 and 35) in these families had the same homozygous PTV, which was considered to partially question the variants' pathogenicity.…”

Section: Introductionmentioning

confidence: 99%

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Biallelic loss-of-function in NRAP is a cause of recessive dilated cardiomyopathy

et al. 2021

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Background Familial dilated cardiomyopathy (DCM) is typically a monogenic disorder with dominant inheritance. Although over 40 genes have been linked to DCM, more than half of the patients undergoing comprehensive genetic testing are left without molecular diagnosis. Recently, biallelic protein-truncating variants (PTVs) in the nebulin-related anchoring protein gene (NRAP) were identified in a few patients with sporadic DCM. Methods and results We determined the frequency of rare NRAP variants in a cohort of DCM patients and control patients to further evaluate role of this gene in cardiomyopathies. A retrospective analysis of our internal variant database consisting of 31,639 individuals who underwent genetic testing (either panel or direct exome sequencing) was performed. The DCM group included 577 patients with either a confirmed or suspected DCM diagnosis. A control cohort of 31,062 individuals, including 25,912 individuals with non-cardiac (control group) and 5,150 with non-DCM cardiac indications (Non-DCM cardiac group). Biallelic (n = 6) or two (n = 5) NRAP variants (two PTVs or PTV+missense) were identified in 11 unrelated probands with DCM (1.9%) but none of the controls. None of the 11 probands had an alternative molecular diagnosis. Family member testing supports co-segregation. Biallelic or potentially biallelic NRAP variants were enriched in DCM vs. controls (OR 1052, p<0.0001). Based on the frequency of NRAP PTVs in the gnomAD reference population, and predicting full penetrance, biallelic NRAP variants could explain 0.25%-2.46% of all DCM cases. Conclusion Loss-of-function in NRAP is a cause for autosomal recessive dilated cardiomyopathy, supporting its inclusion in comprehensive genetic testing.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Biallelic loss-of-function in NRAP is a cause of recessive dilated cardiomyopathy

et al. 2021

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Exploring the complex spectrum of dominance and recessiveness in genetic cardiomyopathies

Lipov,

Jurgens,

Mazzarotto

et al. 2023

Nat Cardiovasc Res

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Discrete categorization of Mendelian disease genes into dominant and recessive models often oversimplifies their underlying genetic architecture. Cardiomyopathies (CMs) are genetic diseases with complex etiologies for which an increasing number of recessive associations have recently been proposed. Here, we comprehensively analyze all published evidence pertaining to biallelic variation associated with CM phenotypes to identify high-confidence recessive genes and explore the spectrum of monoallelic and biallelic variant effects in established recessive and dominant disease genes. We classify 18 genes with robust recessive association with CMs, largely characterized by dilated phenotypes, early disease onset and severe outcomes. Several of these genes have monoallelic association with disease outcomes and cardiac traits in the UK Biobank, including LMOD2 and ALPK3 with dilated and hypertrophic CM, respectively. Our data provide insights into the complex spectrum of dominance and recessiveness in genetic heart disease and demonstrate how such approaches enable the discovery of unexplored genetic associations.

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