Matroshka and ectopic polymorphisms: Two new classes of DNA sequence variation identified at the Van der Woude syndrome locus on 1q32-q41

Van der Woude syndrome (VWS) is an orofacial clefting disorder with an auto somal dominant pattern of inheritance. In our efforts to clone the VWS gene , 900 kb of genomic sequence from the VWS candidate region at chromosome 1q 32-q41 was analyzed for new DNA sequence variants. We observed that in clon e CTA-321i20 a 7922 by sequence is absent relative to the sequence present in PAC clone RP4-782d21 at positions 1669-9590, suggesting the presence of a deletion/insertion (del/ins) polymorphism. Embedded in this 7922 by regio n was a TTCC short tandem repeat (STR). Genotype analysis showed that both the internal STR and the (del/ins) mutation were true polymorphisms. This i s a novel example of intraallelic variation, a polymorphism within a polymo rphism, and we suggest that it be termed a "Matroshka" polymorphism. Furthe r genetic and DNA sequence analysis indicated that the ancestral state of t he 1669-9590 del/ins polymorphism was the insertion allele and that the ori ginal deletion mutation probably occurred only once. A second class of nove l DNA sequence variation was discovered on chromosome 5 that shared a 328 b y identical sequence with this region on chromosome 1. A single nucleotide polymorphism (SNP) was detected by SSCP using a pair of primers derived fro m the chromosome 1 sequence. Surprisingly, these primers also amplified the identical locus on chromosome 5, and the SNP was only located on chromosom e 5. Since the probe unexpectedly detected alleles from another locus, we s uggest that this type of sequence variant be termed an "ectopic" polymorphi sm. These two novel classes of DNA sequence polymorphisms have the potentia l to confound genetic and DNA sequence analysis and may also contribute to variation in disease phenotypes. Hum Mutat 18:422-434, 2001. (C) 2001 Wiley -Liss, Inc.