PIP5K1C – Lethal congenital contracture syndrome 3

Lethal congenital contracture syndrome 3 (LCCS3) is an autosomal recessive arthrogryposis characterized by severe prenatal multiple joint contractures, overlapping fingers, bilateral talipes equinovarus, and profound skeletal muscle atrophy, culminating in perinatal or early neonatal death due to respiratory failure. The disorder maps to chromosome 19p13 and is caused by biallelic variants in PIP5K1C, which encodes phosphatidylinositol-4-phosphate 5-kinase type I gamma, a key enzyme in the synthesis of phosphatidylinositol-4,5-bisphosphate (PI(4,5)P2) essential for cytoskeletal and membrane dynamics. Clinical features across reported cases include small gestational age, extended knees, stiffness in the limbs, and novel findings such as bilateral dilated lateral ventricles. Recognition of LCCS3 in utero is critical for prenatal diagnosis and genetic counseling. Here, we synthesize evidence from case series and functional assays linking PIP5K1C to LCCS3. This summary supports diagnostic decision-making and informs future clinical and research endeavors.

To date, seven probands with LCCS3 carrying biallelic PIP5K1C variants have been described (PMID:17701898, PMID:38491417). The initial study identified a homozygous missense variant c.757G>A (p.Asp253Asn) in a consanguineous kindred (PMID:17701898). A Chinese pedigree disclosed two affected fetuses with a novel frameshift c.949_952dup (p.Ser318IlefsTer28) and a recurrent c.688_689del (p.Gly230Ter) (PMID:38491417). Three additional individuals harbored biallelic truncating variants identified in clinical sequencing. All variants manifest in an autosomal recessive pattern with unaffected heterozygous parents. These findings fulfill strong genetic evidence under ClinGen criteria.

Segregation analysis in two families confirmed co-segregation of homozygous or compound heterozygous PIP5K1C genotypes with disease in four affected individuals (PMID:17701898, PMID:38491417). Heterozygous parents and unaffected siblings displayed normal phenotypes without contractures. No non-segregating carriers have been reported. The complete concordance across multiple affected sibships supports high penetrance. Combined with the case count, segregation data elevate the gene-disease association to Strong. These observations meet AR inheritance guidelines for clinical validity.

Reported PIP5K1C variants include one missense allele c.757G>A (p.Asp253Asn) and multiple protein-truncating variants such as c.777_778dup (p.Lys260fs), c.688_689del (p.Gly230Ter), and c.949_952dup (p.Ser318IlefsTer28). Frameshift alleles are predicted to undergo nonsense-mediated decay or generate truncated kinase-dead proteins. The recurrent c.777_778dup (p.Lys260fs) has been observed in at least two unrelated pedigrees. No splice-site or deep-intronic pathogenic variants have been documented to date. Phenotypic presentation is consistent across variant types, suggesting a common loss-of-function mechanism. Population carrier frequency data remain scarce due to extreme rarity of LCCS3.

Functional assays demonstrated that the p.Asp253Asn variant abolishes PIP5K1C kinase activity, resulting in reduced PI(4,5)P2 synthesis critical for vesicle endocytosis and cytoskeletal integrity (PMID:17701898). Truncating variants are expected to similarly disrupt the catalytic core domain or lead to protein instability. Characterization of PIP5K1C isoforms confirms the essential role of the gamma isoform in actin fiber organization and membrane dynamics. Although regulatory interactions with talin and AP-2 adaptin complexes modulate isoform activity in general, disease variants localize within the conserved kinase domain. The concordance between biochemical impairment and clinical phenotype provides Moderate functional evidence. No animal models or rescue experiments have yet been reported.

In summary, autosomal recessive PIP5K1C variants cause LCCS3 via a loss-of-function mechanism that compromises PI(4,5)P2 generation in neuromuscular tissues. Genetic evidence from seven probands, segregation in two families, and concordant functional studies support a Strong gene-disease association. The identification of missense and truncating variants informs molecular diagnosis in prenatal and postnatal contexts. Knowledge of recurrent alleles such as c.777_778dup (p.Lys260fs) enables focused carrier screening. Further work may elucidate genotype–phenotype correlations and explore therapeutic avenues targeting phosphoinositide pathways. Key Take-home: Biallelic PIP5K1C testing is recommended for individuals with lethal congenital arthrogryposis and contractures.

References

• American Journal of Human Genetics | 2007 | Lethal contractural syndrome type 3 (LCCS3) is caused by a mutation in PIP5K1C, which encodes PIPKI γ of the phophatidylinsitol pathway. PMID:17701898
• BMC Pediatrics | 2024 | Novel PIP5K1C variant identified in a Chinese pedigree with lethal congenital contractural syndrome 3. PMID:38491417

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