Supplementary Material for: Co-occurrence of variants in 3 genes in a patient with congenital skeletal dysplasia and cardiac anomalies: Diagnostic Challenge Posed by a Blended Phenotype

Introduction: Blended phenotypes resulting from the contribution of two or more genetic variants to the disease of a patient pose a significant diagnostic challenge. Correlating between the phenotypes and the genotypes of the affected patients is difficult in these cases, especially in the absence of a large family segregating the condition. Case presentation: We report a child born to consanguineous Syrian parents with a complex phenotype including a skeletal dysplasia, characterized by a small thorax and phalangeal shortening, as well as cardiac anomalies, and sensorineural hearing loss. Molecular analysis identified the presence of three potentially disease-causing genetic variants. These include homozygous variants in the IHH and TTC12B genes, known to be associated with Acrocapitofemoral Dysplasia (OMIM# 607778) and a form of Short-Rib Thoracic Dysplasia (OMIM# 613819), respectively, in addition to a heterozygous variant in the COL11A1 gene, associated with dominant forms of skeletal dysplasia, such as Marshall (OMIM# 154780) and Stickler (OMIM# 608481) syndromes, and hearing loss (OMIM# 618533).
Conclusion: We propose that the complex phenotype observed in the patient results from the contribution of l three of these variants. This case highlights some of the challenges encountered in the genetic counseling of families with rare genetic conditions.