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1.  A Novel Locus for Adolescent Idiopathic Scoliosis on Chromosome 12p 
Adolescent idiopathic scoliosis (AIS) is a common disorder with strong evidence for genetic predisposition. Quantitative trait loci (QTLs) for AIS susceptibility have been identified on chromosomes. We performed a genome-wide genetic linkage scan in 7 multiplex families using 400 marker loci with a mean spacing of 8.6 centiMorgans (cM). We used Genehunter Plus to generate linkage statistics, expressed as homogeneity (HLOD) scores, under dominant and recessive genetic models. We found a significant linkage signal on chromosome 12p, whose support interval extends from near 12pter, spanning approximately 10 million bases or 31 cM. Fine mapping within the region using 20 additional markers reveals maximum HLOD = 3.7 at 5 cM under a dominant inheritance model, and a split peak maximum HLOD = 3.2 at 8 and 18 cM under a recessive inheritance model. The linkage support interval contains 95 known genes. We found evidence suggestive of linkage on chromosomes 1, 6, 7, 8, and 14. This study is the first to find evidence of an AIS susceptibility locus on chromosome 12. Detection of AIS susceptibility QTLs on multiple chromosomes in this and other studies demonstrate that the condition is genetically heterogeneous.
PMCID: PMC4120267  PMID: 19340878
AIS; axial skeletal growth; chromosome 12p; genetic heterogeneity; susceptibility locus
5.  A founder mutation in the Ashkenazi Jewish population affecting mRNA splicing of the CCM2 gene is associated with Cerebral Cavernous Malformations 
Cerebral Cavernous Malformations (CCM) can occur sporadically or are caused by mutations in one of three identified genes. CCM often remain clinically silent until a mutation carrier suffers a stroke or seizure. Pre-symptomatic genetic testing has been valuable to follow and manage CCM mutation carriers. During routine diagnostic testing we identified a 2-base pair change in seven unrelated people of Ashkenazi Jewish (AJ) heritage. Due to the location of the variant beyond the invariant splice donor sequence, the change was reported as a variant of unknown significance. In this study we determined whether this change was a disease-causing mutation and whether it represents a founder mutation in the Ashkenazi Jewish population.
Transcripts arising from the normal and mutant alleles were examined by RT-PCR from affected and unaffected AJ CCM family members. A synthetic splicing system using a chimeric exon was employed to visualize the effects of the change on splice donor site utilization.
The 2-base pair change in CCM2, c.30+5_6delinsTT, segregated with affected status in the study families. RT-PCR revealed loss of the transcript allele that was in phase with the mutation. The 2-base pair change, when tested in an in vitro synthetic splicing system, altered splice donor site utilization. Re-sequencing of the genomic region proximal and distal to the CCM2 gene mutation reveal a common SNP haplotype in affected individuals.
The 2-base pair change in CCM2, c.30+5_6delinsTT, disrupts proper splice donor utilization leading to a degraded transcript. SNP haplotype analysis demonstrates that this mutation is due to a founder in the AJ population. These data have the potential to simplify genetic testing for CCM in the AJ population.
PMCID: PMC3132303  PMID: 21543988
Cerebral Cavernous Malformation; CCM2; mRNA splicing; founder mutation; Ashkenazi Jews
12.  Dinucleotide repeat polymorphism at the D18S34 locus 
Nucleic Acids Research  1990;18(11):3431.
PMCID: PMC330986  PMID: 1972571

Results 1-25 (37)