The prevalence and phenotypic range associated with biallelic <scp><i>PKDCC</i></scp> variants

Pagnamenta, Alistair T; Belles, Rebecca S; Salbert, Bonnie Anne; Wentzensen, Ingrid M.; Sacoto, María J. Guillen; Santos, Francis Jeshira Reynoso; Caffo, Alesky; Ferla, Matteo P.; Banos-Pinero, Benito; Pawliczak, Karolina; Makvand, Mina; Najmabadi, Hossein; Maroofian, Reza; Lester, Tracy; Yanez-Felix, Ana Lucia; Villarroel-Cortes, Camilo E; Xia, Fan; Fayez, Khowla Al; Hashem, Amal Al; Shears, Deborah; Irving, Melita; Offiah, Amaka C.; Kariminejad, Ariana; Taylor, Jenny C

doi:10.1111/cge.14324

Cited by 3 publications

(16 citation statements)

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“…The reported fetus herein was just the rst case reported RLSDF in China. Since the nding of RLSDF at the year of 2018, 11 cases in total containing our patient have been reported [1,2]. Most reported cases were linked to rhizomelia of upper limb (100%), short stature (80%), hypertelorism (66.67%), at face (66.67%), micrognathia (55.56%), short fth digit (50%), hearing loss (50%), high and broad forehead (50%), macrocephaly (42.86%), sloping shoulders (33.33%), patellofemoral dislocation(33.33%) and prominent eyes (30%) with the rhizomelia of upper limb type being the most commonly reported (Table 2).…”

Section: Discussionmentioning

confidence: 99%

“…Rhizomelic limb shortening with dysmorphic features (RLSDF, OMIM#618821) is a rare autosomal recessive disorder characterized of rhizomelic shortening of lower and upper limbs and changeable dysmorphic features, containing short neck, prominent forehead, macrocephaly, broad or depressed nasal bridge, micrognathia, along with long philtrum. Other features included obesity, mild plagiocephaly, laryngomalacia, short thumbs, mild bilateral conductive hearing loss, acanthosis nigricans, central hypotonia and mildly delayed myelination [1,2]. This disease results from biallelic variants inside PKDCC gene that is located in chromosome 2p21 and has 7 exons.…”

Section: Introductionmentioning

confidence: 99%

“…This disease results from biallelic variants inside PKDCC gene that is located in chromosome 2p21 and has 7 exons. It encodes an integrated component of Hedgehog signaling demanded for normal chondrogenesis and bone development [2]. Researches by mice indicate that Hedgehog signalling is capable of being regulated by Pkdcc (also known as Vertebrate lonesome kinase, Vlk) [3].…”

Section: Introductionmentioning

confidence: 99%

“…To date, only 9 families with molecularly con rmed variants in PKDCC gene have been reported [1,2]. The genotype-phenotype correlation of RLSDF is still not clear [2].…”

Section: Introductionmentioning

confidence: 99%

“…To date, only 9 families with molecularly con rmed variants in PKDCC gene have been reported [1,2]. The genotype-phenotype correlation of RLSDF is still not clear [2]. There is no speci c treatment for RLSDF Life expectancy of individuals with RLSDF does not to be affected.…”

Section: Introductionmentioning

confidence: 99%

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Prenatal diagnosis identifies compound heterozygous variants in PKDCC that causes Rhizomelic Limb Shortening with Dysmorphic Features in a Chinese fetus

Yan¹,

Cao²,

Zhang³

et al. 2023

Preprint

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Background: Rhizomelic limb shortening with dysmorphic features (RLSDF) has already been a disorder of the rare autosomal recessive skeletal dysplasia, just having a few reported cases. RLSDF is caused by PKDCC gene variants. In this article, the clinical features and potential RLSDF molecular etiology in a Chinese fetus are depicted. Methods: Genomic DNA (gDNA) extracted from the fetal muscle tissue and parents’ peripheral blood was subjected to chromosomal microarray analysis (CMA) and trio-based whole exome sequencing (Trio-WES). The candidate pathogenic variants were verified by Sanger sequencing. Results: Trio-WES identifed two compound heterozygous variants in PKDCC, c.346delC (p.Pro117Argfs*113) and c.994G>T (p.Glu332Ter), inherited from the father and mother, respectively. Both variants are classified as pathogenic according to ACMG guidelines. Conclusions: It was reported the first prenatal case of PKDCC caused RLSDF among Chinese population. Our findings extended the variation spectrum of PKDCC and emphasized the necessity of WES for early diagnosis of fetuses with skeletal dysplasia and other ultrasound structural abnormalities.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

“…To date, only 9 families with molecularly con rmed variants in PKDCC gene have been reported [1,2]. The genotype-phenotype correlation of RLSDF is still not clear [2].…”

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 3 more Smart Citations

Prenatal diagnosis identifies compound heterozygous variants in PKDCC that causes Rhizomelic Limb Shortening with Dysmorphic Features in a Chinese fetus

Yan¹,

Cao²,

Zhang³

et al. 2023

Preprint

View full text Add to dashboard Cite

show abstract

Prenatal diagnosis of a skeletal disorder characterized by rhizomelic shortening of limbs caused by compound heterozygous variants in the PKDCC gene: Case report and literature review

Wang,

Yu,

Zhang

et al. 2024

Molec Gen & Gen Med

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BackgroundThe protein kinase domain containing cytoplasmic (PKDCC) gene (OMIM#618821) is associated with bone development. Biallelic variants in the PKDCC gene can cause rhizomelic limb shortening with dysmorphic features.Case ReportA fetus was found to be rhizomelic limb shortening at 16 weeks of gestation and amniocentesis was performed at 19 weeks of gestation. Genomic DNA extracted from the amniotic fluid was subjected to chromosomal microarray analysis (CMA), and Trio‐total whole‐exome sequencing (Trio‐WES). Sanger sequencing was used to verify the candidate pathogenic variants. CMA was normal, while Trio‐WES identified two compound heterozygous variants in the PKDCC gene, namely c.417_c.423delCGGCGCG insTCATGGGCTCAGTACAC(p.G140fs*35) and c.345G>A (p.W115*,379). Then the fetus was aborted and the development of its bone cells were compared with that of a normal fetus of similar gestational age by histopathological examination. Clinical findings of the fetus were shortening humerus and femur, synophrys, much hair on the side face, simian line on the right palm, etc. Histopathological examination showed that the affected fetus had increased proliferative chondrocytes, widened proliferative bands, and delayed bone mineralization.ConclusionsWe reported a prenatal case of rhizomelic shortening of limbs caused by compound heterozygous variants in the PKDCC gene, which emphasized the important role of Trio‐WES for diagnosis of skeletal dysplasia in fetuses.

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Prenatal diagnosis to identify compound heterozygous variants in PKDCC that causes rhizomelic limb shortening with dysmorphic features in a fetus from China

Yan,

Cao,

Zhang

et al. 2023

BMC Med Genomics

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Background Rhizomelic limb shortening with dysmorphic features (RLSDF) has already been a disorder of the rare autosomal recessive skeletal dysplasia, just having a few reported cases. RLSDF is caused by protein kinase domain containing, cytoplasmic(PKDCC)gene variants. In this study, we describe the clinical features and potential RLSDF molecular etiology in a fetus from China. Methods Genomic DNA (gDNA) extracted from the fetal muscle tissue and parents’ peripheral blood was subjected to chromosomal microarray analysis (CMA) and trio-based whole exome sequencing (Trio-WES). The candidate pathogenic variants were verified by using Sanger sequencing. Results Trio-WES identified two compound heterozygous variants in PKDCC, c.346delC (p.Pro117Argfs*113) and c.994G > T (p.Glu332Ter), inherited from the father and mother, respectively. Both variants are classified as pathogenic according to American College of Medical Genetics and Genomics guidelines. Conclusions We reported the first prenatal case of RLSDF caused by PKDCC in the Chinese population. Our findings extended the variation spectrum of PKDCC and emphasized the necessity of WES for the early diagnosis of skeletal dysplasia and other ultrasound structural abnormalities in fetuses.

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The prevalence and phenotypic range associated with biallelic PKDCC variants

Abstract: PKDCC encodes a component of Hedgehog signalling required for normal chondrogenesis and skeletal development. Although biallelic PKDCC variants have Genomics England Research Consortium information is given in Data S1.

Cited by 3 publications

References 12 publications

Prenatal diagnosis identifies compound heterozygous variants in PKDCC that causes Rhizomelic Limb Shortening with Dysmorphic Features in a Chinese fetus

Prenatal diagnosis identifies compound heterozygous variants in PKDCC that causes Rhizomelic Limb Shortening with Dysmorphic Features in a Chinese fetus

Prenatal diagnosis of a skeletal disorder characterized by rhizomelic shortening of limbs caused by compound heterozygous variants in the PKDCC gene: Case report and literature review

Prenatal diagnosis to identify compound heterozygous variants in PKDCC that causes rhizomelic limb shortening with dysmorphic features in a fetus from China

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