Novel Compound-Heterozygous Variants in PYCR1 Expand the Variant Spectrum of Autosomal Recessive Cutis Laxa.

BACKGROUND AND OBJECTIVES: Autosomal recessive cutis laxa (ARCL) is a genetically heterogeneous group of connective-tissue disorders characterized by loose, inelastic skin and variable systemic involvement. Biallelic variants in PYCR1 are associated with PYCR1-related ARCL, including ARCL type IIB (OMIM #612940) and type IIIB (OMIM #614438). We aimed to characterize the clinical and molecular findings in one affected family and provide segregation and variant-specific functional evidence for two previously unreported PYCR1 variants. METHODS: The proband and family underwent whole-exome sequencing with copy-number analysis and Sanger confirmation. The splice-site variant was evaluated by qualitative RT-PCR and Sanger sequencing of endogenous peripheral-blood PYCR1 transcripts, whereas the frameshift variant was studied in a heterologous expression system by qPCR and Western blotting. Neuroimaging, exploratory EEG spectral analysis, and public developmental transcriptomic/single-cell resources were used for complementary phenotypic context. RESULTS: The 16-year-old proband had thin lax skin with prominent superficial veins, generalized joint hypermobility, facial dysmorphism, reduced muscle bulk, and motor developmental delay. Chinese WAIS-IV showed a markedly uneven profile (VCI 52; PRI 94; FSIQ 75). Two previously unreported PYCR1 variants were identified in trans: maternally inherited NM_006907.4:c.139-1G>A and paternally inherited NM_006907.4:c.724_725del, p.(Leu242AlafsTer31). Endogenous RNA analysis identified exon 3 skipping associated with c.139-1G>A (r.139_318del), predicting p.(Met48_Lys107del). The c.724_725del construct showed consistently reduced steady-state abundance of the truncated PYCR1 protein relative to WT across three independent experiments. Both variants were classified as likely pathogenic using the ACMG/AMP framework with relevant ClinGen refinements. Brain MRI revealed irregular morphology of the anterior corpus callosum. DISCUSSION: These two previously unreported variants extend the PYCR1 variant spectrum and are supported by complementary segregation, RNA-level, and protein-level evidence. The neurodevelopmental observations provide additional phenotypic context and are interpreted descriptively.