PKD1L1‐related situs inversus associated with sideroblastic anemia

Rodriguez, S; Chaturvedi, Rajiv; Blanchette, Victor S.; Dell, Sharon D.; Axford, Michelle; Cada, Michaela; Dror, Yigal

doi:10.1111/cge.13512

Cited by 5 publications

(6 citation statements)

References 2 publications

(2 reference statements)

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“…PKD1L1 is a subunit of the heterodimeric TRP channel thought to regulate calcium currents ( Delling et al, 2013 ) and is important for confining the NODAL expression to the left side during the left–right axis determination ( Grimes et al, 2016 ). The PKD1L1 p.Arg2555* and p.Ser2646* variants we identified in this study are located at the extracellular domains before the trans-membrane domains 8 and 10 respectively ( Rodriguez et al, 2019 ; Correa et al, 2021 ). These two compound heterozygous changes identified in this study could affect the function of trans-membrane domains 8–10, extracellular domains between them, and an intracellular coiled–coil domain, which interacts with PKD2.…”

Section: Discussionmentioning

confidence: 76%

Spectrum of Genetic Variants in a Cohort of 37 Laterality Defect Cases

et al. 2022

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Laterality defects are defined by the perturbed left–right arrangement of organs in the body, occurring in a syndromal or isolated fashion. In humans, primary ciliary dyskinesia (PCD) is a frequent underlying condition of defective left–right patterning, where ciliary motility defects also result in reduced airway clearance, frequent respiratory infections, and infertility. Non-motile cilia dysfunction and dysfunction of non-ciliary genes can also result in disturbances of the left–right body axis. Despite long-lasting genetic research, identification of gene mutations responsible for left–right patterning has remained surprisingly low. Here, we used whole-exome sequencing with Copy Number Variation (CNV) analysis to delineate the underlying molecular cause in 35 mainly consanguineous families with laterality defects. We identified causative gene variants in 14 families with a majority of mutations detected in genes previously associated with PCD, including two small homozygous CNVs. None of the patients were previously clinically diagnosed with PCD, underlining the importance of genetic diagnostics for PCD diagnosis and adequate clinical management. Identified variants in non-PCD-associated genes included variants in PKD1L1 and PIFO, suggesting that dysfunction of these genes results in laterality defects in humans. Furthermore, we detected candidate variants in GJA1 and ACVR2B possibly associated with situs inversus. The low mutation detection rate of this study, in line with other previously published studies, points toward the possibility of non-coding genetic variants, putative genetic mosaicism, epigenetic, or environmental effects promoting laterality defects.

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Section: Discussionmentioning

confidence: 76%

Spectrum of Genetic Variants in a Cohort of 37 Laterality Defect Cases

et al. 2022

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“…There is no apparent genotype-phenotype correlation (Figure 1D). Our foetuses showed a previously described variant c.8005C > T (p.Arg2669Ter) affecting the extracellular domain between transmembrane domains 10 and 11 (Rodriguez et al, 2019). The other variant, c.160+1G > A, is novel in splice donor site leading to an alteration in splicing.…”

Section: Discussionmentioning

confidence: 61%

“…Presentation with hydrops in congenital heart block has not been described in previous reports of PKD1L1 ‐related heterotaxy (Le Fevre et al., 2019). It could also result from an underlying concurrent congenital sideroblastic anaemia (Rodriguez et al., 2019). There was no evidence of fetal anemia as a normal middle cerebral artery peak systolic velocity was present.…”

Section: Discussionmentioning

confidence: 99%

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Hydrops fetalis in PKD1L1‐related heterotaxy: Report of two foetuses and expanding the phenotypic and molecular spectrum

Correa

Endrakanti

Naini

et al. 2021

Annals of Human Genetics

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Abnormalities in the normal left-right axis asymmetry range from situs inversus totalis to situs ambiguous or heterotaxy. More than 80 genes have been describedto have a role in the establishment of the normal situs of the internal organs. Pathogenic variants in the PKD1L1 gene have recently been described in heterotaxy and congenital heart disease. Till date, 11 families have been described with PKD1L1-related heterotaxy. We describe the first Indian family with two affected foetuses with PKD1L1-related nonimmune hydrops, congenital heart disease, situs inversus, and heterotaxy, with biallelic variants in the compound heterozygous state.

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“…This included nine novel variants in six genes, namely RAPSN , NEB , ASCC1 , GUSB , PKD1L1 , and PIEZO1 . Additionally, previously reported variants were detected in ASCC1 , PKD1L1 , and TAZ 29–32 . Salient clinical features and the putative variants are provided in Table 2.…”

Section: Resultsmentioning

confidence: 99%

Utility of fetal whole exome sequencing in the etiological evaluation and outcome of nonimmune hydrops fetalis

et al. 2021

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Introduction Nonimmune hydrops fetalis (NIHF) has varied etiology. We assessed the etiological spectrum and evaluated the utility of fetal whole exome sequencing (fWES) for the diagnosis of NIHF. Methods In this prospective cohort study, we evaluated antenatally diagnosed fetuses with NIHF between July 2018 and December 2019 according to the routine diagnostic algorithm. Fetuses that remained undiagnosed after routine NIHF workup were subjected to fetal chromosomal microarray and/or WES. Pregnancies were followed up for clinical outcomes. Results Of the 45 fetuses, consanguinity and recurrent hydrops fetalis were observed in 13.3% (6/45) and 28.8% (13/45), respectively. Overall, an etiological diagnosis was possible in 75.5% (34/45) of fetuses, while the cause remained unknown in 24.4% (11/45). A genetic etiology was identified in 46.6% (21/45): aneuploidy and monogenic disorders in 28.8% (13/45) and 17.8% (8/45), respectively. fWES on 19 fetuses detected disease‐causing variants in 42.1% (8/19). Nine novel variants were detected in RAPSN, ASCC1, NEB, PKD1L1, GUSB, and PIEZO1. Only 8.8% (4/45) of the cohort survived without morbidity. Conclusions This study describes the etiological spectrum and the disease‐causing variants in an Indian cohort of hydropic fetuses.

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PKD1L1‐related situs inversus associated with sideroblastic anemia

Cited by 5 publications

References 2 publications

Spectrum of Genetic Variants in a Cohort of 37 Laterality Defect Cases

Spectrum of Genetic Variants in a Cohort of 37 Laterality Defect Cases

Hydrops fetalis in PKD1L1‐related heterotaxy: Report of two foetuses and expanding the phenotypic and molecular spectrum

Utility of fetal whole exome sequencing in the etiological evaluation and outcome of nonimmune hydrops fetalis

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