GRINL1A Complex Transcription Unit Containing GCOM1, MYZAP, and POLR2M Genes Associates with Fully Penetrant Recessive Dilated Cardiomyopathy

Background: Familial dilated cardiomyopathy (DCM) is a monogenic disorder typically inherited in an autosomal dominant pattern. We have identified two Finnish families with familial cardiomyopathy that is not explained by a variant in any previously known cardiomyopathy gene. We describe the cardiac phenotype related to homozygous truncating GCOM1 variants.Methods and Results: This study included two probands and their relatives. All the participants are of Finnish ethnicity. Whole-exome sequencing was used to test the probands; bi-directional Sanger sequencing was used to identify the GCOM1 variants in probands’ family members. Clinical evaluation was performed, medical records and death certificates were obtained. Immunohistochemical analysis of myocardial samples was conducted. A homozygous GCOM1 variant was identified altogether in six individuals, all considered to be affected. None of the nine heterozygous family members fulfilled any cardiomyopathy criteria. Heart failure was the leading clinical feature, and the patients may have had a tendency for atrial arrhythmias.Conclusions: This study demonstrates the significance of GCOM1 variants as a cause of human cardiomyopathy and highlights the importance of searching for new candidate genes when targeted gene panels do not yield a positive outcome.

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Abstract 194: Characterization of Arrhythmogenic Dilated Cardiomyopathy Caused by Novel Filamin C Splice Variant in a Zebrafish Model

Circulation Research ◽

10.1161/res.117.suppl_1.194 ◽

2015 ◽

Vol 117 (suppl_1) ◽

Author(s):

Rene L Begay ◽

Teisha J Rowland ◽

Charles A Tharp ◽

August Martin ◽

Sharon L Graw ◽

...

Keyword(s):

Dilated Cardiomyopathy ◽

Splice Variant ◽

Systolic Dysfunction ◽

Family Members ◽

Muscle Disease ◽

Heart Tube ◽

Zebrafish Model ◽

Cell Stage ◽

Cardiac Phenotype ◽

Filamin C

Although dilated cardiomyopathy (DCM) is a serious and frequent genetic cause of heart failure, only 30-40% of cases can be attributed to a known DCM gene mutation. To identify and confirm additional disease genes involved in DCM, we performed whole exome sequencing in two multigenerational families with DCM, both from the same geographic region of Italy, and found a novel splice variant in the gene encoding filamin-C (FLNC). Previously characterized mutations in FLNC had been primarily linked to skeletal muscle disease, although none of the affected family members displayed skeletal myopathy. To confirm and further characterize the arrhythmogenic DCM phenotype observed in family members, we performed embryonic knockdown experiments using morpholino (MO) treatment in zebrafish (Danio rerio) targeting the FLNC ortholog, filamin Cb (flncb). Following MO injection into 1-2 cell stage zebrafish embryos, 63.4% (78 of 123) of viable flncb MO-injected embryos displayed a cardiac phenotype at 72 hours post fertilization (hpf) (vs. 17.0% [30 of 177] of control MO-injected embryos; p≤0.001). Increases in mortality were observed, with 20.8% (54 of 260) of flncb MO-injected embryos surviving at 7 days post fertilization (vs. 65% [162 of 249] of control embryos; p≤0.001). The flncb MO-injected embryos demonstrated pericardial edema, dysmorphic or dilated cardiac chambers, and abnormal looping of the heart tube suggestive of systolic dysfunction. The flncb MO-injected embryos additionally demonstrated a lower mean stroke volume than controls (0.076 vs. 0.181 nl; p=0.015), a reduced mean cardiac output (10.8 vs. 25 nl/min; p=0.02), and an increase in the fraction of retrograde blood flow over the cardiac cycle (0.42 vs. 0.03; p=0.027). Overall, this flncb MO treatment recapitulated a DCM phenotype similar to the state caused by the human splicing variant, supporting haploinsufficiency as the mechanism leading to DCM in these families. Our findings suggest that approaches to augment endogenous filamin C protein levels may represent a viable treatment strategy that warrants exploration in future studies.

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Familial dilated cardiomyopathy associated with pathogenic TBX5 variants: Expanding the cardiac phenotype associated with Holt–Oram syndrome

American Journal of Medical Genetics Part A ◽

10.1002/ajmg.a.61635 ◽

2020 ◽

Vol 182 (7) ◽

pp. 1725-1734 ◽

Cited By ~ 1

Author(s):

Jenny Patterson ◽

Caroline Coats ◽

Ruth McGowan

Keyword(s):

Dilated Cardiomyopathy ◽

Familial Dilated Cardiomyopathy ◽

Cardiac Phenotype

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Periodic rescreening is indicated for family members at risk of developing familial dilated cardiomyopathy

Journal of the American College of Cardiology ◽

10.1016/s0735-1097(02)01788-6 ◽

2002 ◽

Vol 39 (9) ◽

pp. 1503-1507 ◽

Cited By ~ 29

Author(s):

Kathy A Crispell ◽

Emily L Hanson ◽

Kelly Coates ◽

Warren Toy ◽

Ray E Hershberger

Keyword(s):

At Risk ◽

Dilated Cardiomyopathy ◽

Family Members ◽

Familial Dilated Cardiomyopathy

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Familial dilated cardiomyopathy: An improved diagnostic criterion to assign family members as affected

Journal of Cardiac Failure ◽

10.1016/s1071-9164(98)90165-8 ◽

1998 ◽

Vol 4 (3) ◽

pp. 44

Author(s):

Ray E Hershberger ◽

Hanyu Ni ◽

Kathy Crispell ◽

Anita Wray

Keyword(s):

Dilated Cardiomyopathy ◽

Family Members ◽

Familial Dilated Cardiomyopathy ◽

Diagnostic Criterion

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The importance of preconception and prenatal genetic evaluation in heart transplant individuals and fetal and postnatal cardiac monitoring in their offspring

Cardiology in the Young ◽

10.1017/s1047951118001191 ◽

2018 ◽

Vol 28 (11) ◽

pp. 1356-1358

Author(s):

Yin Liu ◽

Matthew J. Bock ◽

June-Anne Gold

Keyword(s):

Dilated Cardiomyopathy ◽

Heart Transplant ◽

Left Ventricular ◽

Cardiac Monitoring ◽

Idiopathic Dilated Cardiomyopathy ◽

Transplant Recipients ◽

Severe Left Ventricular Dysfunction ◽

Familial Dilated Cardiomyopathy ◽

Familial Cardiomyopathy ◽

Heart Transplant Recipients

AbstractA 24-year-old woman with a history of idiopathic dilated cardiomyopathy status post heart transplant gave birth to a healthy term female infant. At 5 months of age, the infant was diagnosed with severe left ventricular dysfunction with an ejection fraction of 18% and moderate non-compaction of the left ventricle. She received a heart transplant at 7 months of age. Familial dilated cardiomyopathy was diagnosed. Genetic testing revealed a likely pathogenic variant in the TPM1 gene. Fetal cardiac screening is critical for offspring of heart transplant recipients, especially when the reason for transplant was cardiomyopathy. Early genetic consultation and counselling is necessary for all heart transplant recipients, preferably prenatally. Postnatal screening of offspring is essential at birth, at 3-month intervals until 1 year of age, and then annually until the risk for familial cardiomyopathy is assessed.

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