Introduction:
Causal and modifier genes associated with left ventricular noncompaction (LVNC) often occurring in conjunction with other familial cardiomyopathies remain elusive.
Hypothesis:
The LVNC-associated di- and multigenic abnormalities can be identified by whole exome sequencing (WES).
Methods:
Five families with a history of LVNC, including five affected probands, three affected family members, and twelve unaffected relatives, were studied. Genomic DNA was extracted from whole blood samples followed by WES and Sanger sequencing to confirm possibly pathogenic variants predicted by
in-silico
analysis. Phenotype-genotype correlation and quantitative co-segregation studies are performed.
Results:
We identified nine missense possibly pathogenic variants, a 2-bp frameshift insertion, and a 9-bp in-frame insertion in the five families. Two affected siblings in Family 1 were found carrying digenic heterozygous variants: c.4048G>A (p.E1350K) in
MYH7
and c.827C>T (p.A276V) in
ANKRD1.
Unaffected parents were carriers for each of the two variants. Three affected members, father and two daughters, of Family 2 carried c.550A>C (p.K184Q) variant in
MYH7
in contrast to two unaffected members, mother and another daughter. In Family 3, multigenic heterozygosity (c.673G>T (p.D225Y) in
CACNA2D1
; c.440T>A (p.V147E) in
COQ4
and c.3700C>A (p.H1234N) in
MYH7)
was identified in the proband. These variants were found in none of three unaffected relatives. The proband of Family 4 was positive for heterozygous variants: c.2684_2685insAG (p.A897Kfs*3) in
DSC2
, c.8633T>C (p.V2878A) in
OBSCN
, and c.11717C >T (p.T3906I) in
PLEC.
The T3906I PLEC variant was identified in his unaffected half-sibling and his father, but not in his mother. In Family 5, c. 2591A>T (p.D864V) in
HDAC9
, c.9616C>T (p.R3206W) in
PLEC
and c.954_955insT (p.L319Sfs*74) in
MYH14
were identified in the proband. None of those variants were identified in his unaffected sibling.
Conclusions:
We report several potential pathogenic LVNC-associated variants in novel genes (ANKRD1, DSC2,
OBSCN
,
PLEC, HDAC9, MYH14, COQ4, CACNA2D1)
and known genes (
MYH7
and
MYH7B).
The diverse profile of inheritance (digenic and multigenic heterogeneity) that may cause and modify the heterogeneous LVNC phenotypes.
Whole-Exome Sequencing Reveals
GATA4
and
PTEN
Mutations as a Potential Digenic Cause of Left Ventricular Noncompaction
