We describe four unrelated, nonconsanguinous Ashkenazi Jewish families with an identical c.1167insA mutation in FKTN
associated with WWS and a consistently severe phenotype. This c.1167insA mutation is located within a repeat of eight As and is likely the result of slippage of DNA polymerase. The c.1167insA mutation was previously described by Manzini et al
. in three Ashkenazi Jewish families that had the same homozygous insertion in three affected children. Further analysis showed a carrier frequency of 2/299 (0.7%) in a control Ashkenazi population in Israel (Manzini et al., 2008
). This c.1167insA mutation has also been previously described in combination with other FKTN
mutations. A Japanese patient with severe FCMD had the 3kb retrotransposon insertion allele along with c.1167insA on the other allele (Watanabe et al., 2005
). Two families diagnosed with a novel form of limb girdle muscular dystrophy (LGMD2L) without brain abnormalities were compound heterozygous for the c.1167insA mutation (Godfrey et al., 2006
). Two siblings were compound heterozygotes for the c.1167insA mutation and a novel missense mutation c.920G > Ain FKTN
. In another family, a child was heterozygous for the c.1167insA mutation and 1363delG. The siblings were children of Jewish-Indian origin, and the other family was from Israel. It is likely that the c.1167insA mutation in these last two families represents the same founder mutation we describe. In contrast, all five patients in our report were homozygous for the c.1167insA mutation, and all had a severe clinical presentation of prenatal onset. Thus, we conclude that homozygosity for the c.1167insA mutation is associated with a consistently severe WWS phenotype. The prenatal phenotype seen across the cases included hydrocephalus, cerebellar hypoplasia, cobblestone lissencephaly, intrauterine growth restriction, cataracts, and other eye malformations ().The differential diagnosis for this set of manifestations includes MEB disease, FCMD, CMD 1C with structural brain involvement, and other lissencephalies (MillerDieker syndrome, X-linked lissencephaly with agenesis of the corpus callosum, and Norman Roberts syndrome). However, in WWS, the most consistent findings that are prenatally observable are the characteristic brain malformations, which should prompt testing for the c.1167insA mutation in Jewish families.
Table 1 Summary of clinical findings in WWS case reports. Cases A-1, A-2, B-1, and D-1were all diagnosed prenatally through ultrasonographic imaging techniques. Patients A-1, A-2, B-1, C-1, and D-1 all had brain malformations, ophthalmologic abnormalities, and (more ...)
We demonstrated by haplotype analysis that the c.1167insA mutation is a founder Ashkenazi Jewish mutation common to all four unrelated families. Our observed carrier frequency of the c.1167insA FKTN allele was 2/299 (0.7%) in unrelated normal American Ashkenazi Jewish subjects and was similar to the carrier frequency determined in Ashkenazi Jews in Israel. The identification of this Ashkenazi Jewish mutation for such a genetically heterogeneous condition should greatly simplify molecular genetic testing in this population and allow for prenatal diagnosis after identification of ultrasound findings which should be present in the second trimester. Although the carrier frequency for the c.1167insA mutation is low, it should be considered for addition to the Ashkenazi Jewish carrier panel given the severity of the disease and lack of effective intervention.