Choroideremia: close linkage to DXYS1 and DXYS12 demonstrated by segregation analysis and historical‐genealogical evidence

Abstract

Linkage studies using restriction fragment length polymorphisms were conducted in the X‐linked disorder, choroideremia, designated TCD for Progressive Tapeto‐Choroidal Dystrophy. Previously demonstrated close linkage with locus DXYS1 was confirmed (lod 11.44 at 0 recombination distance). In addition, locus DXYS12 was found to be closely linked with TCD (lod 3.31 at 0 recombination distance). The disease mainly occurs in three large kindreds in remote Northern Finland. While formal genealogical proof is lacking, all presently living (more than 80 affected males and 120 carrier females) probably originate from a common founder couple born in 1644 and 1646, twelve generations ago. All 36 patients and 48 carriers tested from the three kindreds had the same haplotype (TCD/DXYS1, llkb/DXYS12,1.6kb). Given that at least 105 female meioses transmitting TCD have occurred since 1650 in these kindreds, extremely close linkage between TCD, DXYS1 and DXYS12 is suggested. The above haplotype is a very useful diagnostic tool in these TCD families. We suggest that our historical‐genealogical approach to linkage analysis may be possible elsewhere in similar isolated populations.

Choroideremia: from genetic and clinical phenotyping to gene therapy and future treatments

“…1 It is estimated that the prevalence of CHM is between 1 in 50,000-100,000 people with a preponderance in the Finish population. [1][2][3][4][5] The disease is inherited in an X-linked recessive pattern with male patients predominantly expressing the characteristic features of early night blindness that evolves into severe peripheral vision loss followed by legal blindness in late adulthood. Female carriers remain mostly asymptomatic although they can experience nyctalopia and exhibit pigmentary changes in the fundus with associated subnormal visual sensitivity.…”

Shades of gray: a comparison of linkage disequilibrium between Hutterites and Europeans

“…The advantages of isolated and founder populations for genetic mapping studies have long been recognized with respect to Mendelian diseases [de la Chapelle 1993; Peltonen 2000], and more recently with respect to common diseases [Heutink and Oostra 2002; Peltonen, et al 2000]; also see Wright, Carothers et al [Wright, et al 1999] for a review of the importance of population choice for study design [Lander and Schork 1994; Sheffield, et al 1998]. Both reduced genetic heterogeneity due to the small number of founders and the increased linkage disequilibrium (LD) due to recent ancestry facilitated the discovery of many rare Mendelian disease genes in founder populations, such as the Finns (e.g., [Nikali, et al 1995; Sankila, et al 1987]), Amish (e.g., [Polymeropoulos, et al 1996; Ruiz-Perez, et al 2000]), Hutterites (e.g. [Boycott, et al 2008; Weiler, et al 1998]), Ashkenazi Jews (e.g., [Anderson, et al 2001; Slaugenhaupt, et al 2001]), Sardinians (e.g., [Verhoeven, et al 2001]), and Icelanders (e.g., [Gulcher, et al 1997]).…”

Live Birth of a Healthy Boy after Preimplantation Genetic Testing for X-Linked Choroideremia Disorder

“…Some months later the normal for the mutation re-vitrified blastocyst was thawed and transferred but the result was negative [26][27][28][29][30][31][32][33][34].…”