Biallelic loss-of-function variants in PLD1 cause congenital right-sided cardiac valve defects and neonatal cardiomyopathy

Lahrouchi, Najim; Postma, Alex V.; Salazar, Christian; Laughter, Daniel M. de; Tjong, Fleur V.Y.; Piherová, Lenka; Bowling, Forrest Z.; Zimmerman, Dominic S; Lodder, Elisabeth M.; Ta‐Shma, Asaf; Perles, Zeev; Beekman, Leander; Ilgun, Aho; Gunst, Quinn D.; Hababa, Mariam; Škorić‐Milosavljević, Doris; Stránecký, Viktor; Tomek, Viktor; Knijff, Peter de; Leeuw, Rick de; Robinson, Jamille Y.; Burn, Sabrina C.; Mustafa, Hiba J.; Ambrose, Matthew; Moss, Timothy J.; Jacober, Jennifer; Niyazov, Dmitriy; Wolf, Barry; Kim, Katherine H.; Cherny, Sara; Rousounides, Andreas; Aristidou-Kallika, Aphrodite; Tanteles, George A.; Bruel, Ange‐Line; Denommé‐Pichon, Anne‐Sophie; Francannet, Christine; Ortiz, Damara; Haak, Monique C.; Harkel, Arend D J Ten; Manten, G. T. R.; Dutman, Annemiek C.; Bouman, Katelijne; Magliozzi, Monia; Radio, Francesca Clementina; Santen, Gijs; Herkert, Johanna C.; Brown, H. Alex; Elpeleg, Orly; Hoff, Maurice J.B. van den; Mulder, Barbara J.M.; Airola, Michael V.; Kmoch, Stanislav; Barnett, Joey V.; Clur, S. A.; Frohman, Michael A.; Bezzina, Connie R.

doi:10.1172/jci142148

Cited by 19 publications

(19 citation statements)

References 45 publications

(70 reference statements)

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“…14 In 2021, a study reported 21 unrelated families from various ancestries with biallelic PLD1 variants who presented predominantly with congenital cardiac valve defects. 35 The majority of the variants in the 21 cases were located at the HKD1 and HKD2 domain. In our study, the compound heterozygous variants in Family A, I378fs and R391C, were also located at the HKD1 domain.…”

Section: Discussionmentioning

confidence: 98%

Detection of Novel Pathogenic Variants in Two Families with Recurrent Fetal Congenital Heart Defects

Cai¹,

Tan²,

Wang³

et al. 2023

PGPM

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Background: Congenital heart disease (CHD) is the most common birth defect with strong genetic heterogeneity. To date, about 400 genes have been linked to CHD, including cell signaling molecules, transcription factors, and structural proteins that are important for heart development. Genetic analysis of CHD cases is crucial for clinical management and etiological analysis. Methods: Whole-exome sequencing (WES) was performed to identify the genetic variants in two independent CHD cases with DNA samples from fetuses and their parents, followed by the exclusion of aneuploidy and large copy number variations (CNVs). The WES results were verified by Sanger sequencing. Results: In family A, a compound heterozygous variation in PLD1 gene consisting of c.1132dupA (p.I378fs) and c.1171C>T (p. R391C) was identified in the fetus. The two variants were inherited from the father (c.1132dupA) and the mother (c.1171C>T), respectively. In family B, a hemizygous variant ZIC3: c.861delG (p.G289Afs*119) was identified in the fetus, which was inherited from the heterozygous mother. We further confirmed that these variants PLD1: c.1132dupA and ZIC3: c.861delG were novel. Conclusion:The findings in our study identified novel variants to the mutation spectrum of CHD and provided reliable evidence for the recurrent risk and reproductive care options to the affected families. Our study also demonstrates that WES has considerable prospects of clinical application in prenatal diagnosis.

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Section: Discussionmentioning

confidence: 98%

Detection of Novel Pathogenic Variants in Two Families with Recurrent Fetal Congenital Heart Defects

Cai¹,

Tan²,

Wang³

et al. 2023

PGPM

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“…Both the patients in this study had congenital heart defects (CHDs) mainly on the right side. Previously, recessive variants of PLD1 (phospholipase D1; MIM* 602382) were reported to be associated with right‐sided congenital cardiac valve defects (Ta‐Shma et al, 2017), and recently, Lahrouchi et al confirmed that biallelic loss‐of‐function (LOF) variants of PLD1 caused the right‐sided congenital cardiac valve defects (Lahrouchi et al, 2021). PLD1 is a signal transduction enzyme that hydrolyzes the membrane lipid phosphatidylcholine to generate a second messenger.…”

Section: Discussuonmentioning

confidence: 99%

“…PLD1 is a signal transduction enzyme that hydrolyzes the membrane lipid phosphatidylcholine to generate a second messenger. It is reported that the patients carrying biallelic LOF variants had reduced enzymatic activity (lower than 25%) compared with that of individuals having wild‐type alleles (Lahrouchi et al, 2021). It was also noted that the LOF of PLD1 leads to a suppression of TGF‐β and sonic hedgehog signaling, which might induce arterial pole defects in the developing heart.…”

Section: Discussuonmentioning

confidence: 99%

Interstitial microdeletions of 3q26.2q26.31 in two patients with neurodevelopmental delay and distinctive features

Tamura

Shimojima

Shiihara

et al. 2022

American J of Med Genetics Pt A

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Interstitial microdeletions in the long arm of chromosome 3 are rare. In this study, we identified two patients with approximately 5‐Mb overlapping deletions in the 3q26.2q26.31 region. Both patients showed neurodevelopmental delays, congenital heart defects, and distinctive facial features. One of them showed growth deficiency and brain abnormalities, as shown on a magnetic resonance imaging scan. Haploinsufficiency of NLGN1 and FNDC3B present in the common deletion region was considered to be responsible for neurodevelopmental delay and the distinctive features, respectively. The possibility of unmasked variants in PLD1 was considered and analyzed, but no possible pathogenic variant was found, and the mechanism of the congenital heart defects observed in the patients is unknown. Because 3q26.2q26.31 deletions are rare, more information is required to establish genotype–phenotype correlations associated with microdeletions in this region.

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“…Genetic defects responsible for CHD include aneuploidy (presence of an additional chromosome, absence of a chromosome, or deletion/duplication of one arm of a chromosome), copy number variation (deletion or duplication of a segment of a chromosome), and genetic mutations [ 44 , 45 , 46 ]. To date, pathogenic mutations in over 100 genes have been involved in the occurrence of CHD, of which most encode cardiac transcription factors, cell adhesion molecules, signaling pathway proteins, and cardiac structural proteins essential for cardiovascular morphogenesis [ 44 , 45 , 46 , 48 , 49 , 50 , 51 , 52 , 53 , 54 , 55 , 56 , 57 , 58 , 59 , 60 , 61 , 62 , 63 , 64 , 65 , 66 , 67 , 68 , 69 ]. However, CHD is of pronounced genetic heterogeneity, and the genetic determinants causative for CHD in a significant proportion of cases remain to be identified.…”

Section: Introductionmentioning

confidence: 99%

Discovery of GJC1 (Cx45) as a New Gene Underlying Congenital Heart Disease and Arrhythmias

Wang

et al. 2023

Biology

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As the most prevalent type of birth malformation, congenital heart disease (CHD) gives rise to substantial mortality and morbidity as well as a socioeconomic burden. Although aggregating investigations highlight the genetic basis for CHD, the genetic determinants underpinning CHD remain largely obscure. In this research, a Chinese family suffering from autosomal dominant CHD (atrial septal defect) and arrhythmias was enrolled. A genome-wide genotyping with microsatellite markers followed by linkage assay as well as sequencing analysis was conducted. The functional effects of the discovered genetic mutation were characterized by dual patch-clamp electrophysiological recordings in N2A cells and propidium iodide uptake assays in HeLa cells. As a result, a novel genetic locus for CHD and arrhythmias was located on chromosome 17q21.31-q21.33, a 4.82-cM (5.12 Mb) region between two markers of D17S1861 and D17S1795. Sequencing assays of the genes at the mapped locus unveiled a novel heterozygous mutation in the GJC1 gene coding for connexin 45 (Cx45), NM_005497.4:c.550A>G;p.R184G, which was in co-segregation with the disease in the whole family and was not observed in 516 unrelated healthy individuals or gnomAD. Electrophysiological analyses revealed that the mutation significantly diminished the coupling conductance in homomeric cell pairs (R184G/R184G) and in cell pairs expressing either R184G/Cx45 or R184G/Cx43. Propidium iodide uptake experiments demonstrated that the Cx45 R184G mutation did not increase the Cx45 hemichannel function. This investigation locates a new genetic locus linked to CHD and arrhythmias on chromosome 17q21.31-q21.33 and indicates GJC1 as a novel gene predisposing to CHD and arrhythmias, implying clinical implications for prognostic risk assessment and personalized management of patients affected with CHD and arrhythmias.

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Biallelic loss-of-function variants in PLD1 cause congenital right-sided cardiac valve defects and neonatal cardiomyopathy

Cited by 19 publications

References 45 publications

Detection of Novel Pathogenic Variants in Two Families with Recurrent Fetal Congenital Heart Defects

Detection of Novel Pathogenic Variants in Two Families with Recurrent Fetal Congenital Heart Defects

Interstitial microdeletions of 3q26.2q26.31 in two patients with neurodevelopmental delay and distinctive features

Discovery of GJC1 (Cx45) as a New Gene Underlying Congenital Heart Disease and Arrhythmias

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