ClinVar

Using reverse transcription PCR and chemical mismatch cleavage (CMC), Whitney et al. (1993) demonstrated homozygosity for an identical splice mutation in the FANCC gene in 2 Ashkenazi Jewish patients with Fanconi anemia (FANCC; 227645). Three additional patients bearing this allele were found through screening 21 other families. A single base change in the fourth intronic base changed the sequence from a consensus A to T, resulting in deletion of the 111-bp exon 4. They referred to the allele as IVS4+4, A-to-T.

Whitney et al. (1994) used allele-specific oligonucleotide hybridization to determine the frequency of this mutation in Ashkenazi Jews with Fanconi anemia (FA). They studied 11 patients, each of whom had 2 Jewish parents, and 1 patient who had a Jewish mother and a non-Jewish father. The mutation was found in 19 of the 23 Jewish FA chromosomes (83%), but was not found in 2 other Jewish patients, in 39 non-Jewish patients, or in 130 non-Jewish persons without FA. Two of 315 Jewish individuals without FA were found to be carriers of the mutation. Verlander et al. (1995) developed amplification refractory mutation system (ARMS) assays for 5 known mutations in FAC and used these assays to determine the carrier frequency of the IVS4 +4 A-to-T mutation in an Ashkenazi Jewish population. Among 3,104 Jewish individuals, primarily of Ashkenazi descent, 35 IVS4 carriers were identified, for a carrier frequency of 1 in 89 (1.1%). Among 563 Iraqi Jews, no carriers of the IVS4 mutation were found. They suggested that a founder effect is responsible for the high frequency of the mutation in Ashkenazim and that the carrier frequency of more than 1% justified inclusion of this mutation in the battery of tests routinely provided to the Jewish population.

Verlinsky et al. (2001) presented a means for guaranteeing HLA-matching tissues for stem cell transplantation. The advent of single-cell PCR provided the opportunity for combined preimplantation genetic diagnosis (PGD) and HLA antigen testing. They identified a couple, both carriers of the IVS4+4A-T mutation in the FANCC gene, with an affected child requiring an HLA-compatible donor for cord blood transplantation. They used DNA analysis of single blastomeres to preselect unaffected embryos representing an HLA match for the affected sib. The transfer of mutation-negative, HLA-compatible embryos resulted in the pregnancy and birth of an unaffected child.