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

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.

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.

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.

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.