“Incomplete penetrance” is poorly understood in genetics

Incomplete penetrance” is a term used in genetics to explain why “having the genotype does not always necessarily result in the phenotype (trait). Even more problematic, penetrance might be 10% or 80%. And the phenotype might be a Mendelian disorder or a multifactorial trait. This concern also exists in predicting drug response (efficacy vs toxicity) as well as any response to an environmental toxicant (“Is it ‘safe’ or ‘unsafe’ to the individual based on his/her genotype, and, to what degree?”)

This article (and accompanying editorial) discuss an attempt to elucidate and understand a small portion of incomplete penetrance.    

Congenital heart defects (CHDs) affect 2%–3% of newborns and remain challenging clinically. There is an ongoing project to elucidate the causes of CHDs, focusing primarily on genetics as dictated by the epidemiology. In the paper [below], Santos and colleagues describe studies of Cornelia de Lange syndrome-associated secundum atrial septal defects (ASDs) caused by NIPBL mutations, undertaken with a targeted trapping allele in mice. They show that Nipbl haploinsufficiency in either of two cell populations is sufficient to engender ASDs. However, that expression alone, in either one of those populations, is sufficient to rescue the disorder. This study provides novel insights into incomplete penetrance and oligogenic effects underlying CHDs.

Article: Conditional Creation and Rescue of Nipbl-Deficiency in Mice Reveals Multiple Determinants of Risk for Congenital Heart Defects
Rosaysela Santos, Shimako Kawauchi, Russell E. Jacobs, Martha E. Lopez-Burks, Hojae Choi, Jamie Wikenheiser, Benedikt Hallgrimsson, Heather A. Jamniczky, Scott E. Fraser, Arthur D. Lander, Anne L. Calof

Use of conditional/invertible genetic technology in a mouse model of Cornelia de Lange Syndrome shows that the risk of congenital heart defects depends on complex interactions among cell lineages inside and outside the heart. Read the associated Primer.

Editocial The Hole and the Whole: Lessons from Manipulation of Nipbl Deficiency
Bruce D. Gelb

Incomplete penetrance is poorly understood in genetics. This Primer assesses a new study which provides new insights into that phenomenon using an animal model of Cornelia de Lange syndrome.

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