BACKGROUND: Genetic testing can determine those at risk for hereditary haemochromatosis (HH) caused by HFE mutations before the onset of symptoms. However, there is no optimum screening strategy, mainly owing to the variable penetrance in those who are homozygous for the HFE Cys282Tyr (C282Y) mutation. The objective of this study was to identify the majority of individuals at serious risk of developing HFE haemochromatosis before they developed life threatening complications. METHODS: We first estimated the therapeutic penetrance of the C282Y mutation in people living in la Somme, France, using genetic, demographic, biochemical, and follow up data. We examined the benefits of neonatal screening on the basis of increased risk to relatives of newborns carrying one or two copies of the C282Y mutation. Between 1999 and 2002, we screened 7038 newborns from two maternity hospitals in the north of France for the C282Y and His63Asp (H63D) mutations in the HFE gene, using bloodspots collected on Guthrie cards. Family studies and genetic counselling were undertaken, based on the results of the baby's genotype. FINDINGS: In la Somme, we found that 24% of the adults homozygous for the C282Y mutation required at least 5 g iron to be removed to restore normal iron parameters (that is, the therapeutic penetrance). In the reverse cascade screening study, we identified 19 C282Y homozygotes (1/370), 491 heterozygotes (1/14) and 166 compound heterozygotes (1/42) in 7038 newborns tested. The reverse cascade screening strategy resulted in 80 adults being screened for both mutations. We identified 10 previously unknown C282Y homozygotes of whom six (four men and two women) required venesection. Acceptance of neonatal screening was high; parents understood the risks of having HH and the benefits of early detection, but a number of parents were reluctant to take the test themselves. Neonatal screening for HH is straightforward. Reverse cascade screening increased the efficiency of detecting affected adults with undiagnosed haemochromatosis. This strategy allows almost complete coverage for HH and could be a model for efficient screening for other late onset genetic diseases.
BACKGROUND: Genetic testing can determine those at risk for hereditary haemochromatosis (HH) caused by HFE mutations before the onset of symptoms. However, there is no optimum screening strategy, mainly owing to the variable penetrance in those who are homozygous for the HFE Cys282Tyr (C282Y) mutation. The objective of this study was to identify the majority of individuals at serious risk of developing HFEhaemochromatosis before they developed life threatening complications. METHODS: We first estimated the therapeutic penetrance of the C282Y mutation in people living in la Somme, France, using genetic, demographic, biochemical, and follow up data. We examined the benefits of neonatal screening on the basis of increased risk to relatives of newborns carrying one or two copies of the C282Y mutation. Between 1999 and 2002, we screened 7038 newborns from two maternity hospitals in the north of France for the C282Y and His63Asp (H63D) mutations in the HFE gene, using bloodspots collected on Guthrie cards. Family studies and genetic counselling were undertaken, based on the results of the baby's genotype. FINDINGS: In la Somme, we found that 24% of the adults homozygous for the C282Y mutation required at least 5 g iron to be removed to restore normal iron parameters (that is, the therapeutic penetrance). In the reverse cascade screening study, we identified 19 C282Y homozygotes (1/370), 491 heterozygotes (1/14) and 166 compound heterozygotes (1/42) in 7038 newborns tested. The reverse cascade screening strategy resulted in 80 adults being screened for both mutations. We identified 10 previously unknown C282Y homozygotes of whom six (four men and two women) required venesection. Acceptance of neonatal screening was high; parents understood the risks of having HH and the benefits of early detection, but a number of parents were reluctant to take the test themselves. Neonatal screening for HH is straightforward. Reverse cascade screening increased the efficiency of detecting affected adults with undiagnosed haemochromatosis. This strategy allows almost complete coverage for HH and could be a model for efficient screening for other late onset genetic diseases.
Authors: C Anne McCune; Layla N Al-Jader; Alison May; Sara L Hayes; Helen A Jackson; Mark Worwood Journal: Hum Genet Date: 2002-09-26 Impact factor: 4.132
Authors: Martin B Delatycki; Michelle Wolthuizen; Veronica Collins; Elizabeth Varley; Joanna Craven; Katrina J Allen; Lyle C Gurrin; Maryanne Aitken; M Kaye Trembath; Lyndal Bond; Gabrielle R Wilson; Sarah E M Stephenson; Ivan Macciocca; Chriselle Hickerton; Paul J Lockhart; Sylvia A Metcalfe Journal: Eur J Hum Genet Date: 2012-01-11 Impact factor: 4.246
Authors: Carlos J Gallego; Amber Burt; Agnes S Sundaresan; Zi Ye; Christopher Shaw; David R Crosslin; Paul K Crane; S Malia Fullerton; Kris Hansen; David Carrell; Helena Kuivaniemi; Kimberly Derr; Mariza de Andrade; Catherine A McCarty; Terrie E Kitchner; Brittany K Ragon; Sarah C Stallings; Gabriella Papa; Joseph Bochenek; Maureen E Smith; Sharon A Aufox; Jennifer A Pacheco; Vaibhav Patel; Elisha M Friesema; Angelika Ludtke Erwin; Omri Gottesman; Glenn S Gerhard; Marylyn Ritchie; Arno G Motulsky; Iftikhar J Kullo; Eric B Larson; Gerard Tromp; Murray H Brilliant; Erwin Bottinger; Joshua C Denny; Dan M Roden; Marc S Williams; Gail P Jarvik Journal: Am J Hum Genet Date: 2015-09-10 Impact factor: 11.025