Family studies in Gaucher Disease: a key resource for early diagnosis and personalized treatment strategies.

Gaucher Disease (GD) is an inherited metabolic disorder caused by mutations in the GBA1 gene, which is responsible for the synthesis of the enzyme glucocerebrosidase (GCase). The clinical manifestations, which are extremely heterogeneous, include splenomegaly, hepatomegaly, anaemia and bone complications. GD is an autosomal recessive condition, meaning that the clinical phenotype manifests itself only in the presence of two mutated alleles, which are inherited from both parents, who are generally healthy and asymptomatic. However, other family members (brothers, sisters, grandparents, uncles, aunts, cousins) may be heterozygous carriers or, in some cases, present with undiagnosed forms. In order to identify these individuals and monitor their health, it is essential to conduct family segregation studies. These are often disregarded in clinical practice, despite their crucial role in understanding the distribution of the disease. In this study, a comprehensive diagnostic analysis was conducted on four families, including biochemical and genetic investigations. In the first three families, an affected proband was identified, exhibiting characteristic symptoms, reduced enzyme activity and increased substrate, associated with the presence of two causative mutations. Segregation studies revealed additional affected individuals or carriers, some of whom were completely asymptomatic or had mild manifestations. In the fourth family, the investigation started with a paternal uncle who was found to be a heterozygous carrier. The study was extended to non-direct relatives, which allowed the identification of other affected individuals who would otherwise have remained undiagnosed. These results emphasise the significance of extended family analysis, encompassing second-and third-degree relatives, as a fundamental instrument for comprehension of the hereditary distribution of GD and for the timely identification of individuals at risk. The exclusion of non-direct relatives from genetic screening represents a significant missed opportunity for timely diagnosis, effective clinical management, and family planning.