Abstracts

Rationale: AMRF, an autosomal recessive form of progressive myoclonus epilepsy with renal failure, was initially described in three French Canadian families in 1986. Subsequently, additional families were reported in the USA, Cuba, Germany, Portugal and Australia. Disease onset is usually in the late teens or early twenties, and begins with tremor and proteinuria, progressing to action myoclonus, tonic-clonic seizures and renal failure, requiring dialysis and/or renal transplantation. The gene for this disease was recently found to be SCARB2/Limp2, encoding a lysosomal-membrane protein. A nonsense mutation c.862C>T (Q288X) in exon 7 of SCARB2 was identified in both parents of one of the original French-Canadian patients. The aim of this study was to characterize the SCARB2 mutations in French Canadian patients with AMRF and their family members, and to determine whether these mutations can be explained by a founder effect. Methods: The original French Canadian families were contacted and family histories updated. Additional families were also ascertained. DNA was obtained on 85 family members in 5 families, and exon 7 of the SCARB2 gene was sequenced for the Q288X mutation. The genealogies of the AMRF carriers sharing this mutation were reconstructed and analyzed using the BALSAC population register. Haplotype analysis employing highly heterozygous markers was also performed. Results: All five original AMRF patients have died. Four new patients in two families were homozygous for the Q288X mutation. In one of the new families, both parents are second degree cousins to one of the original probands and to one another. Twenty-eight unaffected individuals in four families who were not obligate carriers were found to be heterozygous for the Q288X mutation. This included one carrier couple, who were later found to have an affected son and to be related 6 generations back. Over 20 other married-in spouses of these mutation carriers had negative sequencing of the entire SCARB2 gene. In a fifth family, the mother of one of the original patients was found to carry another SCARB2 mutation, suggesting allelic heterogeneity. Genealogies of the 4 families sharing the same mutation have been traced to the beginning of the 17th century. To date, three links have been found among the families 6 generations back, and one 9 generations back. The mean kinship coefficient was significantly higher than in control French Canadian genealogies. Haplotype analysis in the region of the SCARB2 gene resulted in a shared haplotype of over 7.2 Mb involving 6 heterozygous markers, strongly suggesting identity by descent. Conclusions: By combining genealogical and molecular data sets, we have established that four French Canadian families who were previously not known to be related share the same SCARB2 mutation that can be explained by a founder effect. Carrier screening for the founder mutation in this population can be carried out without sequencing the entire SCARB2 gene. This has important implications for genetic counseling, prenatal and preclinical diagnosis, and prevention of this debilitating disease.