Non-syndromic polydactyly has been associated with pathogenic variants in 11 genes until today, including IQCE gene. More precisely, loss-of-function of IQCE is associated with the autosomal recessive disorder postaxial polydactyly type A7 (PAPA7, MIM #617642). A 3-year-old female patient was referred to our genetics department with postaxial polydactyly, syndactyly, brachydactyly, and hypoplastic teeth. Through whole-exome sequencing (WES), a pathogenic IQCE variant was identified (c.895_904del) in the homozygous state, which adequately explained the disease phenotype of our patient. However, copy number variant (CNV) analysis from WES data, using ExomeDepth, revealed a novel, likely pathogenic large deletion involving IQCE genomic regions (DEL:chr7:2606751_2641098) encompassing exons 2-18 of the gene. IQCE gene codes for a 695-amino acid protein located at the base of the primary cilia that positively regulates the Hedgehog signaling pathway. This case report represents the first description of a large deletion in IQCE and indicates that implementation of ExomeDepth in routine WES analysis can contribute valuable information toward elucidating the correct etiology of rare genetic diseases, increasing the diagnostic yield, and minimizing the need for additional tests.

A 7-year-old female presented with blepharophimosis ptosis epicanthus inversus syndrome with congenital hypothyroidism and brachydactyly. She displayed typical manifestations of type II blepharophimosis ptosis epicanthus inversus syndrome (normal uterus position, ovarian volume, and normal serum hormone levels). She takes levothyroxine sodium daily due to her congenital hypothyroidism. Karyotype analysis and genetic analysis of FOXL2 coding sequence was found to be normal. mtDNA A3243G, A8344G, 8993, and 13513 genes were also normal. The absence of mutations excluded mitochondrial encephalomyopathies. To the best of our knowledge, this is the first reported case of blepharophimosis ptosis epicanthus inversus syndrome with congenital hypothyroidism and brachydactyly.