Exploring the phenotypic spectrum and osteopenia mechanisms in Yunis-Varón syndrome.

Purpose: Biallelic variants in or are associated with Yunis-Varón syndrome (YVS), which is characterized by multisystem involvement including skeletal findings, craniofacial dysmorphisms and central nervous system anomalies. Pathogenic variants in those same genes have also been associated with a predominantly neurological phenotype and with nonsyndromic conditions, such as Charcot-Marie-Tooth disease and amyotrophic lateral sclerosis. By describing 5 new cases of -associated YVS and reviewing the literature, we better delineate the clinical phenotype associated with loss of function of those genes. We also explore osteopenia mechanisms by assessing bone physiologic parameters in a mouse model.

Methods: Exome sequencing or Sanger sequencing was performed in 5 unrelated individuals. Bone histomorphometry was performed in mice and compared with wild type. Relevant literature from the last 10 years was reviewed.

Results: All individuals presented a phenotype overlapping the typical YVS and the brain anomalies and neurologic syndrome. Clinical features included developmental delay, structural brain malformations, and skeletal anomalies, such as osteopenia. Biallelic variants were identified in each individual. In mice, bone histomorphometry parameters suggested that osteopenia might be secondary to reduced bone formation rather than increased bone degradation.

Conclusion: This study contributes to a better understanding of the phenotypic variability caused by pathogenic variants in or and suggests an important overlap between previously described phenotypes. The brain anomalies and neurologic syndrome is likely in the same spectrum as classical YVS. Further studies are still needed to clarify the effects of partial loss-of-function (hypomorphic) variants and to identify genotype-phenotype correlations.