The mode of inheritance
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Inheritance of a genetic disease is important to know as it enables to predict the risks of developing a disease depending on the parents status towards the genetic condition.
Inheritance is classically studied by making pedigrees in which affected and non affected individuals across several generations of a family are reported. Pedigrees often rely on different levels of uncertainty, depending on whether the individuals have clearly been diagnosed or not. In severe conditions especially, people might have deceased before being even diagnosed, and often the establishment of the medical status of the individual only relies on relatives testimonies. Also, to be able to draw a reliable conclusion from these pedigrees, you have to study a sufficiently large number of family members, which gets tricky when dealing with rare diseases such as vEDS. Prevalence of vEDS is currently estimated to be of about 1:200 000 xxx check consistency with figures from Hannah, despite many people being possibly undiagnosed yet (Pepin et al., 1999).
The mode of inheritance of vEDS has been identified in a study published by Johnson and Falls in 1949 (Johnson and Falls, 1949). This study demonstrated autosomal dominant inheritance of vEDS in an extensive kindred comprising 32 patients over 6 generations. At this time the difference between the various EDS presentations was still not made though. Previous studies did already evoke autosomal dominant inheritance for cases of EDS, but the reported families were never studied over more than 4 generations, which limited the reliability of the conclusions.
Autosomal dominant inheritance means that having only one of the two copies of the gene at stake being mutated is sufficient to give rise to the pathological phenotype of vEDS. The vast majority of people affected with vEDS carry only one mutated copy.
Understanding the mode of inheritance of a disease is very important especially when providing genetic counseling for couples intending to have a child. Usually, only one of the two individuals is affected with the disease, and there is a 50% total risk of transmitting the mutant allele and not the wild-type one to the child. If both of the two parents were affected, they would have a 25% chance of not transmitting the disease to the child. This is exemplified by the Punnett squares shown below.
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Sometimes none of the two parents are affected, while the child presents vEDS. Unless there is an alternate paternity or maternity, that means that the pathogenic mutation appeared de novo in the very early stage of development (Pepin et al., 1999).
The pedigree of a large Belgian family segregating vEDS in an autosomal-dominant manner is given. We can see that the II.1 individual affected with vEDS transmitted the condition to approximately 50% of his 14 children (Nicholls et al., 1988).
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There are also rare reports of autosomal recessive inheritance which will be discussed later in the section (Jørgensen et al., 2014 ; Plancke et al., 2009).
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References :
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Pepin, M.G. Murray, M.L., Byers, P.H. (1999), ‘Vascular Ehlers-Danlos Syndrome’, Gene Reviews [Internet]
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Johnson, M.D. Falls H.F. (1949), ‘Ehlers-Danlos Syndrome. A Clinical and Genetic Study.’, Arch Derm Syphilol, 60(1):82-105.
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Nicholls, A.C. De Paepe, A.Narcisi, P. Dalgleish, R. De Keyser, F. Matton, M. Pope, F.M. (1988), ‘Linkage of a polymorphic marker for the type III collagen gene (COL3A1) to atypical autosomal dominant Ehlers-Danlos syndrome type IV in a large Belgian pedigree’, Human Genetics, 78, 3:276–281
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Jørgensen, A. Fagerheim, T. Rand-Hendriksen, S. Lunde, P. I. Vorren, T. O. Pepin, M. G. Leistritz, D. F. Byers, P. H. (2014), ‘Vascular Ehlers-Danlos Syndrome in siblings with biallelic COL3A1 sequence variants and marked clinical variability in the extended family.’ European journal of human genetics, 23(6), 796-802.
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Plancke, A. Holder-Espinasse, M. Rigau, V. Manouvrier, S. Claustres, M. Khau Van Kien, P. (2009), ‘Homozygosity for a null allele of COL3A1 results in recessive Ehlers-Danlos syndrome.’ European journal of human genetics, 17(11), 1411-6.
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