Fig. 1: Collagen XXV domain structure, COL25A1 transcript variants, biallelic COL25A1 pathogenic variants, and associated clinical features.

A Schematic representation of the domain structure of collagen XXV/COL25A1 (NP_942014.1; longest isoform). Amino acid numbering is given according to Fig. 3A in ref. [6]. Collagenous domains (COL1 to COL3) are represented by gray boxes and non‐collagenous domains (NC1-4) by black lines. The NC1 domain is composed of an intracellular (intra), a transmembrane (TM, shaded in gray), and an extracellular (extra) region. Dotted lines indicate the exons encoding the COL1-3 domains [according to NM_198721.4—see (B)]. B Schematics of COL25A1 transcript variants in the NCBI and Ensembl databases (last accessed 10/2024), with the MANE select transcript NM_198721.4 highlighted in bold. Exons are represented by boxes, with the coding region in black (in-frame exons) or blue (out-of-frame exons) and untranslated regions in gray; introns are indicated by black lines. The numbering of selected exons is given. Alternatively spliced exons that are only present in transcript variant NM_001256074.3 are indicated in orange. Novel alternatively spliced exons identified in transcriptome sequencing data of 42 fibroblast cDNA samples are indicated by white arrowheads (see Supplementary Fig. S3). NM_001256074.3 is the predominant transcript variant expressed in fibroblasts. C Location of previously published and novel biallelic COL25A1 variants (in bold) is shown below the exon-intron structure. Variant description is given according to the COL25A1 mRNA reference number NM_198721.4. Associated phenotypes are shown on the left, arranged from mild at the top to severe at the bottom. D Phenotypic spectrum from mildest to most severe associated with biallelic COL25A1 variants. The triangle visualizes the increasing severity of the phenotype from isolated ocular manifestations (white; mild phenotype) to complex fetal phenotypes (black; prenatal lethal). Associated clinical features are shown on the right. ^aVariants previously published in patients with CCDD [3]. The deletion chr4:108,931,745–109,055,301 (GRCh38/hg38) [chr4:109,852,901–109,976,457 (GRCh37/hg19)] encompasses exons 4–11 and not only exons 4–10 as reported previously [3]; ^bvariants previously published in patients with AMC with or without CCDD [4]; AMC arthrogryposis multiplex congenita, C C-terminus, CCDD congenital cranial dysinnervation disorder, chet compound heterozygous, hom homozygous, MANE select matched annotation between NCBI (RefSeq) and EBI (Ensembl/GENCODE), N N-terminus, S subject, w/ with, w/o without.