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Fig. 1 Genetic and clinical aspects of affected individuals harboring CACHD1 variants. A. Location of CACHD1 variants in relation to exonic location (top); and domain structure (bottom; GenBank: NM_020925.4, NP_065976.3). CACHD1 consists of an exofacial N terminus, a von Willebrand factor A (VWA) domain, 2 bacterial chemosensory-like cache domains, a short hydrophobic transmembrane domain, and an intracellular C terminus. Exonic variants affect exons 3, 4, and 6. Intronic variants localize in introns 2, 12, and 16. Most variants affect the early portion of the gene, predicted to lead to premature transcription termination and putative NMD. Numbers under the protein schematic indicate amino acid numbers. Cache, Ca2+ channel and chemotaxis receptor; CR, cysteine rich; HR, histidine rich; MIDAS, metal ion-dependent adhesion site; NLS, nuclear localization signal; TM, transmembrane domain. Locations of domains are approximate based on data from www.Uniprot.org. B. Pedigrees of the reported families with the segregation patterns of CACHD1 variants. Open shapes, unaffected individuals; filled shapes, affected individuals; square, male; circle, female, triangle, pregnancy not carried to term; wt, wild type. C. Clinical photographs. Individual #1 at 13 years shows sparse hair, medially sparse eyebrows, a pit on the left cheek, and small and posteriorly rotated ears with preauricular tags, underdeveloped crus of the helix, and uplifted earlobes. Individual #2 at 1 year shows bilateral preauricular skin tags associated with overfolding of the superior helices. Individuals #5 (31+5 weeks) and #6 (21+5 weeks) show long and thick eyebrows, periorbital rings, palpebral edema, low-set ears with dysplastic outer ear and bilateral preauricular skin tags, and macroglossia. D. Graph summarizing the distribution of the most common clinical features (present in at least two cases) in the reported cohort. Abbreviations: CMDTs, congenital malformations of the digestive tract; DD, developmental delay; ID, intellectual disability; NA, not applicable.