Abstract
Background
Biallelic pathogenic variants in PIP5K1C (MIM #606,102) lead to lethal congenital contractural syndrome 3 (LCCS3, MIM #611,369), a rare autosomal recessive genetic disorder characterized by small gestational age, severe multiple joint contractures and muscle atrophy, early death due to respiratory failure. Currently, 5 individuals with LCCS3 were reported and 5 pathogenic variants in PIP5K1C were identified. Here, we reported the two fetuses in a Chinese pedigree who displayed multiple joint contractures and other congenital anomalies.
Methods
Trio-based whole-exome sequencing (WES) was performed for the parents and the recent fetus to detect the genetic cause for fetus phenotype.
Results
A novel variant, NM_012398.3: c.949_952dup, p.S318Ifs*28 and a previously reported variant, c.688_689del, p.G230Qfs*114 (ClinVar database) in PIP5K1C, were detected in the individuals, and these variants were inherited from the mother and father, respectively. We described the features of multiple joint contractures in our fetuses, including bilateral talipes equinovarus, stiffness in the limbs, extended knees, persistently closed hands and overlap** fingers, which have not been delineated detailedly in previously reported LCCS3 individuals. Furthermore, novel phenotype, bilateral dilated lateral ventricles, was revealed in one fetus.
Conclusions
These findings expanded the genetic variant spectrum of PIP5K1C and enriched the clinical features of LCCS3, which will help with the prenatal diagnosis and genetic counseling for this family.
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Background
Lethal congenital contracture syndrome (LCCS) is a heterogenous group of congenital genetic condition. It is characterized by multiple joint contractures, polyhydramnios and reduced fetal movement, often leading to the perinatal or neonatal death. Studies have suggested that LCCS is an autosomal recessive disorder causally linked to 11 genes, including GLE1, ERBB3, PIP5K1C, MYBPC1, DNM2, ZBTB42, CNTNAP1, ADCY6, ADGRG6, NEK9 and GLDN. Among them, LCCS1 (MIM #253,310), LCCS7 (MIM #607,598) and LCCS11 (MIM #617,194) have been relatively frequent reported in the literature [1,2,3,4,5,6]. However, lethal congenital contracture syndrome 3 (LCCS3 MIM #611,369), caused by biallelic pathogenic variants in PIP5K1C (MIM #606,102), was rarely reported.
The PIP5K1C gene consists of 18 exons and encodes a 668-amino acid enzyme. This protein utilizes phosphatidylinositol 4-phosphate (PI4P) as a substrate to synthesize phosphatidylinositol 4,5-phosphate (PIP2) on the cell membrane [7, 1B, II-2). Then, she underwent vaginal delivery prematurely at 26 weeks, and the baby passed away after birth due to respiratory failure. In the recent pregnancy, the woman sought medical attention due to advanced maternal age and progressively reduced fetal movement. At 23 weeks of gestation, a prenatal ultrasound scan revealed bilateral dilated lateral ventricles (13.4 mm). Additionally, the fetus exhibited stiffness in the limbs, extended knees, bilateral talipes equinovarus and persistently closed hands (Fig. 1B, II-4). The karyotype analysis and chromosomal microarray of the amniotic fluid were normal. MLPA detected no deletion of exons 7 and 8 in SMN1.
The pedigree chart and radiographic findings for the two fetuses. (A). Pedigree for a consanguineous Chinese family with LCCS3 (The black arrow represents the proband, translucent grey indicates carrier). (B). Radiographic findings for the two fetuses. (II-2) bilateral talipes equinovarus (a), flexion contractures of fingers and overlap** fingers (b). (II-4) bilateral dilated lateral ventricles (13.4 mm) (c), stiffness in the limbs, extended knees (d), bilateral talipes equinovarus (e) and persistently closed hands (f)
Genetic analysis
Compound heterozygous variants, NM_012398.3: c.949_952dup (p.S318Ifs*28) and c.688_689del (p.G230Qfs*114) in PIP5K1C, were revealed in II-4, which were inherited from the mother and father. Next, we analyzed the DNA sample of II-2, and it expectedly revealed the same PIP5K1C compound heterozygous variants. Sanger sequencing verification was performed for other members in the pedigree. Individual II-1 was proven to be wildtype and individual II-3 was an asymptomatic carrier (c.949_952dup, p.S318Ifs*28 in PIP5K1C). The variant segregates as autosomal recessive (Fig. 2). The paternally inherited frameshift variant, (c.688_689del, p.G230Qfs*114), has been reported in ClinVar database. The maternally inherited novel variant, c.949_952dup (p.S318Ifs*28), was predicted to cause protein truncation and was unlikely escape nonsense-mediated mRNA decay. In addition, the individuals’ phenotypes were highly consistent with that of LCCS3. Trio-based WES also excluded other possible known genetic causes. Thus, both variants were categorized as clinically pathogenic according to the ACMG/AMP guidelines. (PVS1 + PM2 + PP1 + PP4).
Variant confirmation by Sanger sequencing. Compound heterozygous variants NM_012398.3: c.688_689del and c.949_952dup in PIP5K1C were detected in both fetuses and their asymptomatic parents and siblings. The red arrow indicates the variant site
Discussion
PIP5K1C is mainly highly expressed in brain and plays an important role in neural signaling pathway [12, 13]. Pip5k1c -/- mice caused a 50% reduction in PIP2 in brain, leading to an impairment of its depolarization-dependent synthesis in nerve terminals and synaptic defects [14]. PIP5K1C has been demonstrated to regulate various cellular processes including receptor-mediated calcium signaling transmission, actin cytoskeleton dynamics, endocytosis and exocytosis [15]. Additionally, PIP5K1C plays a crucial role in the maintenance of bone development. It exerts its influence on bone growth and development by regulating the movement of calcium ions in cells and body fluids [18, 19], here our two fetuses also exhibited bilateral talipes equinovarus. Ankylosis of knee joint was observed in individuals with LCCS6, 7 and 9, here our fetus 2 (II-4) showed this feature [5, 18, 20]. Flexion contractures of fingers were reported in individuals with LCCS7, 9, 10, 11, which was also observed in our two fetuses [5, 18,19,20,21]. Our findings profiled the picture of multiple joint contractures in LCCS3. Polyhydramnios was a marked feature of LCCS [16,17,18,19,20,21,22,23,24,25]. However, this feature has not yet been observed in individuals with LCCS3, which deserves further investigation.
In conclusion, we described in detail the prenatal clinical features of a Chinese pedigree with LCCS3 caused by biallelic pathogenic variants in PIP5K1C. The identification of the novel variant and novel phenotypes expands the variant spectrum of PIP5K1C and enriches the clinical characteristics of LCCS3, which will be valuable for prenatal diagnosis and genetic counseling.
Data availability
The datasets for this article are not publicly available due to concerns regarding participant/patient anonymity. Requests to access the datasets should be directed to the corresponding author.
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Acknowledgements
We would like to express our sincere gratitude to the pedigree for their cooperation. Furthermore, we extend our thanks to all the colleagues who actively participated in this study.
Funding
This study was supported by the Dongguan Social Development Project (No. 20221800900532 to Jianhua Luo). The funding body participated in the design of the project and interpretation of whole exome sequencing.
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FZ drafted the first versions of the manuscript. HMY and JHL were responsible for the design of the project, data analysis, and revised the manuscript. HMG, ZXD, QHX made the clinical evaluation and collected clinical information of the patients in detail. XLZ provided financial support. QMW performed the experiments and data entry.
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The studies involving human participants were reviewed and approved by ethics committee of Dongguan Maternal and Child Health Hospital. Written informed consent was obtained from the patient’s parents for publication.
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Zhang, F., Guo, H., Zhou, X. et al. Novel PIP5K1C variant identified in a Chinese pedigree with lethal congenital contractural syndrome 3. BMC Pediatr 24, 182 (2024). https://doi.org/10.1186/s12887-024-04674-6
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DOI: https://doi.org/10.1186/s12887-024-04674-6