Familial Screening for the Prevention of Rare Diseases: A Focus on Lipodystrophy in Southern Saudi Arabia

Abstract

Background: Lipodystrophy is a relatively rare, complex disease characterised by a deficiency of adipose tissue and can present as either generalised lipodystrophy (GLD) or partial lipodystrophy (PLD). The prevalence of this disease varies by region. This study aimed to identify the genetic variations associated with lipodystrophy in the southern part of Saudi Arabia.

Methodology: We conducted a retrospective study by recruiting nine patients from six families, recruiting the proband whole exome sequencing results or any other genetic test results, screening other family members using Sanger sequencing and analysing the carrier status of the latter. These patients were recruited from the Endocrinology and Diabetes Clinic at Jazan General Hospital and East Jeddah Hospital, both in the Kingdom of Saudi Arabia.

Result: Eight patients were diagnosed with GLD, and one was diagnosed with PLD. Of the six families, four were consanguineously married from the same tribe, while the remaining belonged to the same clan. The majority of GLD patients had an AGPAT2 c.158del mutation, but some had a BSCL2 c.942dup mutation. The single PLD case had a PPARG c.1024C > T mutation but no family history of the disease. In all families evaluated in this study, some family members were confirmed to be carriers of the mutation observed in the corresponding patient.

Conclusion: Familial screening of relatives of patients with rare, autosomal recessive diseases, such as lipodystrophy, especially when there is a family history, allows the implementation of measures to prevent the onset or reduced severity of disease and reduces the chances of the pathogenic allele being passed onto future generations. Creating a national registry of patients with genetic diseases and carriers of familial pathogenic alleles will allow the assessment of preventive measures and accelerate disease intervention via gene therapy.

Keywords: Common variants; Lipodystrophy; Prevention; Rare diseases; Saudi Arabia.

Fig. 1

Family one’s pedigree with consanguineous marriage. The proband is indicated by the red colour. L.F01.3 was confirmed to be homozygous for c.1558del in AGPAT2, while the parents (L.F01.1 and L.F01.2) were confirmed to be heterozygous

Fig. 2

The second family’s pedigree for consanguineous marriage. The black arrow indicates the problem. The two daughters in the red circles were confirmed to be homozygous for c.1558del in AGPAT2. The father, the twin sons and the grandchild were also confirmed to be homozygous for the same mutation

Fig. 3

The third family’s pedigree with consanguineous marriage. The proband is indicated by a black arrow. Two daughters (L.F03.5 and L.F03.6) were confirmed to be homozygous for c.942dup in BSCL2, while the parents and a sibling (L.F03.1, L.F03.2 and L.F03.3) were confirmed to be heterozygous, with L.F03.4 being an unaffected daughter

Fig. 4

The fourth family’s pedigree with consanguineous marriage. The proband indicated by the black arrow was found to be homozygous for c.158del in the AGPAT2 gene, while both parents were found to be heterozygous

Fig. 5

The fifth family’s pedigree with consanguineous marriage. The proband is indicated with a black arrow and red colour. The two daughters in the red circles (L.F05.3 and L.F05.4) were confirmed to be homozygous for c.1558del in AGPAT2, and the parents and one daughter (L.F05.5) were all confirmed to be heterozygous

Fig. 6

The sixth family’s pedigree with proband L.F06.1 was diagnosed with partial lipodystrophy and indicated with a black arrow. The patient was confirmed to carry a heterozygous mutation for c.1024C > T in PPARG. No other family members were sequenced, and none were reported as having the phenotype