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TABLE 3

Reproductive Risks in Common Genetic Disorders

Genetic DisorderReproductive Risks
Autosomal dominant disorders  
 Achondroplasia: most common form of skeletal dysplasia caused by a mutation in FGFR3 A person with achondroplasia whose partner has normal stature has a 50% chance of having a child with achondroplasia. A pregnant woman with achondroplasia may have difficulty carrying the fetus to term. 
 If both genetic parents have achondroplasia, there is a 25% chance of having an infant with a lethal disorder who has 2 copies of the FGFR3 mutation. 
 Deletion of 22q11: common, with wide spectrum of presentation including intellectual disabilities, mental health issues, congenital heart disease, immunodeficiency, and hypoparathyroidism (formerly called DiGeorge syndrome) A parent with mild learning problems or mental health issues can have a child with more complex birth defects and severe developmental problems. 
 Chromosomal abnormalities, such as microdeletions, are passed on in an autosomal dominant pattern and may have variable severity of the phenotype from one generation to the next. 
 OI: most forms of brittle bone disease are caused by mutations in COL1A1 or COL1A2. Confirmation of the diagnosis of OI can now be made with DNA analysis in blood. 
 Most severe cases of OI arise from de novo mutations, but patients with milder forms of OI have a 50% chance of passing on their mutation in each pregnancy. There are more rare forms of OI caused by autosomal recessive genes with a 25% recurrence risk. 
 EDS: there are now 14 types of EDS The hypermobile type is the most common with an estimated incidence of 1:5000. The genes for this type are unknown. This type can be associated with gastrointestinal tract issues, immunologic changes, dysautonomia, pelvic floor dysfunction, prolapse of the rectum and/or uterine prolapse, and chronic pain and disability. 
 The vascular form of EDS can be associated with severe, life-threatening issues including arterial rupture, intestinal rupture, and uterine rupture in pregnancy. 
Autosomal recessive disorders A history of consanguinity increases the chances of having a partner who carries mutations in the same gene. 
 Genetic boys with cystic fibrosis are sterile. 
 Patients of certain ethnic backgrounds have a higher carrier rate of having mutations in autosomal recessive disorders; there are now next-generation sequencing panels that screen for carriers of certain disorders so that patients can receive genetic counseling regarding their recurrence risks. 
 Many patients with autosomal recessive disorders have more severe disabilities and are less likely to procreate. 
X-linked disorders Females who are carriers of FMR1, which causes fragile X syndrome, have an increased risk of premature ovarian failure. The maternal grandfather may develop a condition that mimics Parkinson disease, called FRAXTAS. 
 The severity of symptoms in female carriers of X-linked disorders may be affected by skewed X-inactivation. 
 A female carrying a mutation in an X-linked gene (eg, fragile X syndrome) may be normal or have just a mild phenotype but has a risk of having a male child with more severe issues. 
Mitochondrial disorders Mitochondrial disorders may be caused by mutations in mitochondrial DNA, in which case they are maternally inherited, or may be caused by mutations in autosomal genes, in which case they are usually autosomal recessively inherited. 
 Maternally inherited mitochondrial disorders are generally passed on to all children in the sibship, although the severity of issues may vary from one sibling to another. 
Multifactorial disorders  
 NTDs are common birth defects with an increased recurrence risk within families Patients with NTDs have an ∼5% chance of having a child with an NTD. 
 Siblings of patients with NTDs, parents, aunts, uncles, etc, also have an increased risk. 
 Folate, 4 mg/kg per day, taken 3 mo before conception and through the first trimester, can decrease (but not eliminate) this risk. 
 Certain ethnic groups (including people of English and/or Irish, Hispanic, and Chinese descent) have an increased risk of having a child with an NTD and might also consider taking folate prophylactically, even without a family history. 
 Other Some disorders are caused by multiple factors including genes that may not be known, teratogens such as alcohol, or nutritional factors such as low folate. Recently available genetic tests including next-generation sequencing panels have helped make specific diagnoses in patients with rare disorders. 
Genetic DisorderReproductive Risks
Autosomal dominant disorders  
 Achondroplasia: most common form of skeletal dysplasia caused by a mutation in FGFR3 A person with achondroplasia whose partner has normal stature has a 50% chance of having a child with achondroplasia. A pregnant woman with achondroplasia may have difficulty carrying the fetus to term. 
 If both genetic parents have achondroplasia, there is a 25% chance of having an infant with a lethal disorder who has 2 copies of the FGFR3 mutation. 
 Deletion of 22q11: common, with wide spectrum of presentation including intellectual disabilities, mental health issues, congenital heart disease, immunodeficiency, and hypoparathyroidism (formerly called DiGeorge syndrome) A parent with mild learning problems or mental health issues can have a child with more complex birth defects and severe developmental problems. 
 Chromosomal abnormalities, such as microdeletions, are passed on in an autosomal dominant pattern and may have variable severity of the phenotype from one generation to the next. 
 OI: most forms of brittle bone disease are caused by mutations in COL1A1 or COL1A2. Confirmation of the diagnosis of OI can now be made with DNA analysis in blood. 
 Most severe cases of OI arise from de novo mutations, but patients with milder forms of OI have a 50% chance of passing on their mutation in each pregnancy. There are more rare forms of OI caused by autosomal recessive genes with a 25% recurrence risk. 
 EDS: there are now 14 types of EDS The hypermobile type is the most common with an estimated incidence of 1:5000. The genes for this type are unknown. This type can be associated with gastrointestinal tract issues, immunologic changes, dysautonomia, pelvic floor dysfunction, prolapse of the rectum and/or uterine prolapse, and chronic pain and disability. 
 The vascular form of EDS can be associated with severe, life-threatening issues including arterial rupture, intestinal rupture, and uterine rupture in pregnancy. 
Autosomal recessive disorders A history of consanguinity increases the chances of having a partner who carries mutations in the same gene. 
 Genetic boys with cystic fibrosis are sterile. 
 Patients of certain ethnic backgrounds have a higher carrier rate of having mutations in autosomal recessive disorders; there are now next-generation sequencing panels that screen for carriers of certain disorders so that patients can receive genetic counseling regarding their recurrence risks. 
 Many patients with autosomal recessive disorders have more severe disabilities and are less likely to procreate. 
X-linked disorders Females who are carriers of FMR1, which causes fragile X syndrome, have an increased risk of premature ovarian failure. The maternal grandfather may develop a condition that mimics Parkinson disease, called FRAXTAS. 
 The severity of symptoms in female carriers of X-linked disorders may be affected by skewed X-inactivation. 
 A female carrying a mutation in an X-linked gene (eg, fragile X syndrome) may be normal or have just a mild phenotype but has a risk of having a male child with more severe issues. 
Mitochondrial disorders Mitochondrial disorders may be caused by mutations in mitochondrial DNA, in which case they are maternally inherited, or may be caused by mutations in autosomal genes, in which case they are usually autosomal recessively inherited. 
 Maternally inherited mitochondrial disorders are generally passed on to all children in the sibship, although the severity of issues may vary from one sibling to another. 
Multifactorial disorders  
 NTDs are common birth defects with an increased recurrence risk within families Patients with NTDs have an ∼5% chance of having a child with an NTD. 
 Siblings of patients with NTDs, parents, aunts, uncles, etc, also have an increased risk. 
 Folate, 4 mg/kg per day, taken 3 mo before conception and through the first trimester, can decrease (but not eliminate) this risk. 
 Certain ethnic groups (including people of English and/or Irish, Hispanic, and Chinese descent) have an increased risk of having a child with an NTD and might also consider taking folate prophylactically, even without a family history. 
 Other Some disorders are caused by multiple factors including genes that may not be known, teratogens such as alcohol, or nutritional factors such as low folate. Recently available genetic tests including next-generation sequencing panels have helped make specific diagnoses in patients with rare disorders. 

COL1A1, collagen type I alpha 1; COL1A2, collagen type I alpha 2; EDS, Ehlers-Danlos syndrome; FGFR3, fibroblast growth factor receptor 3; FRAXTAS, fragile X-associated tremor/ataxia syndrome; NTD, neural tube defect; OI, osteogenesis imperfecta.

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