A Japanese patient with Teebi hypertelorism syndrome and a novel CDH11 EC1 domain variant

Abstract

AbstractThe gene CDH11 encodes cadherin‐11, a Type II cadherin superfamily member that contains five extracellular cadherin (EC) domains. Cadherin‐11 undergoes trans‐dimerization via the EC1 domain to generate cadherin complexes. Compound heterozygous and homozygous loss‐of‐function CDH11 variants are observed in Elsahy–Waters syndrome (EWS), which shows characteristic craniofacial features, vertebral abnormalities, cutaneous syndactyly in 2–3 digits, genitourinary anomalies, and intellectual disability. Heterozygous CDH11 variants can cause Teebi hypertelorism syndrome (THS), which features widely spaced eyes and hypospadias. We report a THS patient with a novel CDH11 variant involving the EC1 domain. The patient was a 10‐month‐old male with normal developmental milestones, but had widely spaced eyes, strabismus, hypospadias, shawl scrotum, broad thumbs (right bifid thumb in x‐ray), polysyndactyly of the left fourth finger, and cutaneous syndactyly of left third/fourth fingers. Exome sequencing identified a de novo heterozygous CDH11 variant (NM_001797.4:c.229C > T [p.Leu77Phe] NC_000016.9:g.64998856G > A). Clinical features were consistent with previously reported THS patients, but polysyndactyly, broad thumb, and cutaneous syndactyly overlapped phenotypic features of EWS. THS and EWS may represent a spectrum of CDH11‐related disorders. Residue Leu77 in this novel CDH11 variant lines a large hydrophobic pocket where side chains of the partner cadherin‐11 insert to trans‐dimerize, suggesting that the cadherin‐11 structure might be altered in this variant.