June 2020
Volume 61, Issue 7
Free
ARVO Annual Meeting Abstract  |   June 2020
Segregation Distortion, “gene cheating”, in families with North Carolina Macular Dystrophy (MCDR1/NCMD)
Author Affiliations & Notes
  • Fadi Shaya
    Ophthalmology, Macula and Retina Institute, Glendale, California, United States
    Molecular Insight Research Foundation, Glendale and Los Angeles, California, United States
  • Nitin Udar
    Ophthalmology, Macula and Retina Institute, Glendale, California, United States
    Molecular Insight Research Foundation, Glendale and Los Angeles, California, United States
  • Brent Zanke
    Arctic Medical Laboratories, Grand Rapids, Michigan, United States
  • Kent W Small
    Ophthalmology, Macula and Retina Institute, Glendale, California, United States
    Molecular Insight Research Foundation, Glendale and Los Angeles, California, United States
  • Footnotes
    Commercial Relationships   Fadi Shaya, None; Nitin Udar, None; Brent Zanke, None; Kent Small, None
  • Footnotes
    Support  Foundation Fighting Blindness Grant #: BR-GE-1216-0715-CSH
Investigative Ophthalmology & Visual Science June 2020, Vol.61, 4464. doi:
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      Fadi Shaya, Nitin Udar, Brent Zanke, Kent W Small; Segregation Distortion, “gene cheating”, in families with North Carolina Macular Dystrophy (MCDR1/NCMD). Invest. Ophthalmol. Vis. Sci. 2020;61(7):4464.

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      © ARVO (1962-2015); The Authors (2016-present)

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Abstract

Purpose : North Carolina Macular Dystrophy (NCMD/MCDR1) is a congenital autosomal dominant and completely penetrant disease involving the development of the macula. Clinically, one of the hallmarks of NCMD is the great phenotypic variability. During the initial search for genetic linkage, 90% of the human genome had been excluded by Small et al., in 1990 which stimulated a search for non-Mendelian influences that might violate the traditional parametric assumptions in linkage analysis. Herein, we evaluated more NCMD families for evidence of segregation distortion, “gene cheating” , to determine if the initial finding in the single large family (family 765) held true.

Methods : The inclusion criteria was for families who had two or more affected individuals with clinical and genotypic findings consistent with NCMD. The number of affected males and females was counted as well the number of affected subjects with an affected mother and with an affected father. To determine the 95% confidence interval of an observed proportion, the method of Newcome and Davis was utilized with a continuity correction reflecting the discreet nature of ratios derived from observations in individuals. The analysis was performed using a VasserStats proportions calculator to determine the probability distribution of observed proportions.

Results : The 95% confidence interval for the observed ratio of NCMD with affected fathers to affected mothers was 0.3418-0.4781. Since this doesn’t contain 0.5, it can be concluded that there is a statistical difference. A p value derived from the normal distribution was 0.0021, indicating that more affected cases have affected mothers than affected fathers.

Conclusions : Our new larger dataset supports our earlier finding from 1990 with the single large family from North Carolina (family #765) that an affected female is more likely to transmit the affected allele to their children than an affected male. This is a violation of Mendel’s law of independent assortment. However, this violation of parametric linkage analysis did not prevent successful linkage mapping of NCMD. Indeed, the peak LOD score using several NCMD families generated a peak LOD score of 41, which is one of the highest LOD scores ever generated in human genetics.

This is a 2020 ARVO Annual Meeting abstract.

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