Lekárska genetika a diagnostika 1/2024

The first case of Cousin syndrome with autosomal dominant inheritance

Introduction: Developmental dysplasia of the hip represents a wide spectrum of morphological deviations and resulting functional disorders in different stages of the severity of their pathology. The etiology of the disease is associated with many genetic and environmental risk factors. The genetic basis of the disease can be based on a group of genes leading to the development of an isolated form of the disease or from systemic genetic changes affecting the skeleton. Genetic diagnosis is very difficult in these cases due to high genetic and phenotypic heterogeneity. Case: In our case report, we deal with revealing the genetic etiology of bilateral dislocation of the hip joint with onset in the neonatal period and a positive family history. The clinical picture of the disease in the proband was dominated by short stature, astigmatism and a mild degree of facial dysmorphia. We identified a pathogenic variant in the TBX15 gene in a heterozygous state by genetic examination of a complex panel of genes associated with skeletal dysplasias of the method of massive parallel sequencing on the NextSeq 550 device. The causality of the identified variant was confirmed by segregation analysis by examining several family members, while the presence of the variant was associated with the occurrence of the disease in the proband‘s family. Disorders in the TBX15 gene lead to Cousin‘s syndrome, which in terms of prevalence is one of the ultra-rare diseases. The occurrence of the mentioned syndrome is described in current medical literature only in the case of inactivation of both alleles of the TBX15 gene and in association with autosomal recessive inheritance. However, we confirmed the occurrence of a variant on only one allele in our patient as well as in family members showing the disease. The presence of other genetic changes or major genomic changes was excluded. Conclusion: This is the first case of Cousin‘s syndrome with an autosomal dominant type of inheritance. Gene TBX15 belongs to a family of transcription factors with known sensitivity to the gene dosage effect. Inactivation of only one allele can thus lead to a milder phenotype. The results of our work significantly change the view of Cousin‘s syndrome, which until now was considered a relatively easily recognizable entity with significant facial dysmorphism and typical radiological signs.

Keywords: developmental dysplasia of the hip, genetic diagnosis, massive parallel sequencing, TBX15 gene, Cousin syndrome