Recurrent IGFALS gene mutations p.E35Gfs*17 and p.[L409F;A475V]: hot spot or founder effect?

SCAGLIA, PAULA; SALA, ANDREA; BERGADA, IGNACIO; BRASLAVSKY, DEBORA; KESELMAN, ANA; CASTRO, ANGELA ESPINOSA; DOMENE, SABINA; JASPER, HECTOR; CORACH, DANIEL; DOMENE, HORACIO

Barcelona

Congreso; 54th. Annual European Society for Pediatric Endocrinology Meeting; 2015

European Society for Pediatric Endocrinology

Background: Some IGFALS variants have been reported in more than one ALS-deficient family raising the question whether they originated from a single common ancestor allele (founder effect) or alternatively, as independent mutational events (hot spot). Since c.103dupG (p.E35Gfs*17) is located in a stretch of 5 consecutive guanine residues, where both G-duplication and deletion have been described in several families, we speculate that this region could be a hot spot. In contrast, c.[1225C>T;1424C>T] (p.[L409F;A475V]) variants, both present in the same allele in two unrelated families, could result from a founder effect.Objective and hypotheses: To test the hypothesis of a founder effect vs. hot spot by studying polymorphic variants surrounding IGFALS gene and uniparental lineage markers in families harboring the c.103dupG and c.[1225C>T;1424C>T] variants.Method: We sequenced the whole IGFALS gene and characterized 2 STRs flanking IGFALS gene locus in 30 individuals from 6 unrelated families, 2 harboring the c.[1225C>T;1424C>T] variants and 4 carriers of c.103dupG. Nine informative SNPs and 2 STRs were used to define the specific haplotype associated to the mutation (D16S3435/9 SNPs/D16S3024). In addition, patri- and matrilineal lineages were analyzed by means of 23 Y-STRs typing and mtDNA-D-Loop sequencing.Results: Four families carrying the c.103dupG variant presented the same STRs and SNPs microhaplotype (CA)12/gtcggtgcc/(CA)21 while all the c.[1225C>T;1424C>T] carriers of the other 2 families presented a different microhaplotype (CA)15/acgaaccgt/(CA)22 or (CA)23. Phylogenetic analysis revealed that all male lineages can be attributed to European or Eurasian haplogroups (50% E1b1b; 33% R1b and 17% Q) while mtDNA lineage belonged to Native American (56%), African (22%) and European (22%) haplogroups.Conclusion: Based on this number of families studied, the finding of two particular microhaplotypes support the hypothesis of a founder effect for both variants, c.103dupG (p.E35Gfs*17) and c.[1225C>T;1424C>T] (p.[L409F;A475V]); each originating from two independent ancestor alleles.