Genetic Disorders and the Fetus. Группа авторов

disorders may need to be considered in the quest to determine the cause of infertility including, for example, the blepharophimosis, ptosis, epicanthus inversus syndrome, which may respond to treatment.⁵¹⁶

      In a study of 75,784 women to determine all‐cause and cause‐specific mortality, those with infertility had a 10 percent increased risk of death from any cause.⁵¹⁷ Death from breast cancer was more than doubled. In a major prospective Danish study, 3,356 women who had children born after frozen embryo transfer were compared with 910,291 fertile women. The incidence rate of childhood cancer was 17.5 per 100,000 for children born to fertile women, and 44.4 per 100,000 in children born after the use of frozen embryos.⁵¹⁸ The statistically significant increased risk was primarily leukemia and sympathetic nervous system tumors. The cause(s) remain unknown. A US study did not find a significant association, but had a shorter follow‐up period (<5 years), follow‐up loss, and incomplete maternal data.⁵¹⁹ In a retrospective study using insurance data, the records of 19,658 infertile women and 525,695 fertile women were examined to determine severe maternal morbidity.⁵²⁰ The overall incidence of severe maternal morbidity among women receiving fertility treatment was 7.0 percent compared with 4.3 percent in fertile women.

      Parental carrier of a genetic disorder

      Prospective healthy parents are mostly unaware of their carrier status for a chromosomal or single‐gene disorder, unless their medical or reproductive history has otherwise been informative. Studies to determine prenatal carrier status for a chromosomal disorder are recommended following a history of recurrent miscarriage, previous stillbirth, previous child with intellectual disability, or congenital abnormality, infertility, oligospermia, azoospermia, or a family history that is concerning for any of these outcomes. Chromosome analysis will mostly suffice in determining translocations, inversions, and somatic mosaicism. Chromosomal microarrays (see Chapter 13) for both parents are appropriate if no diagnosis was made for previous affected progeny, but will miss balanced translocations.

The first preconception visit is the time to establish the carrier status of a couple for either a chromosomal or monogenic disorder.⁵²¹ Among the many items to be considered during the preconception visit are the potential physical features indicative of sex‐linked disorders that may manifest in female carriers (see discussion later). With or without a family history of the disorder in question, referral to a clinical geneticist would be appropriate for final evaluation of possible implications. Failure to recognize obvious features in a manifesting female may well result in a missed opportunity for prenatal genetic studies and an outcome characterized by a seriously affected male (or occasionally female) offspring. Recognition of the carrier status for Duchenne muscular dystrophy (DMD) of a prospective mother at the first preconception visit should immediately include consideration of her own future health. Some two‐thirds of mothers are carriers of a DMD gene mutation. As X‐linked carriers they may manifest symptoms and signs of this disorder, including muscle weakness, prominent but weak calf muscles, abnormal gait, fatigue, exercise intolerance, and, of greatest importance, heart involvement.⁵²² Up to 16.7 percent of DMD carriers develop dilated cardiomyopathy, with carriers of Becker muscular dystrophy (BMD) having up to a 13.3 percent risk.⁵²³ The cardiomyopathy may also manifest with conduction defects and arrhythmias.^{522, 524–527} While most carriers become symptomatic around puberty,⁵²⁸ the risks and severity increase with age. Unfortunately, physicians are often unaware of the risks DMD carriers face,⁵²⁹ despite having elevated levels of creatine phosphokinase.⁵³⁰ In a study of 77 DMD and BMD carriers with a molecular confirmed diagnosis, 49 percent had myocardial fibrosis detected by cardiac MRI.⁵³¹ Irreversible heart failure maybe the final complication for which cardiac transplantation has been done.⁵³²

      A report on 355 fragile X carrier women noted that >30 percent complained of anxiety, depression, and headaches.⁵³³ Between 20 and 30 percent of carriers experience irregular or absent menses due to primary ovarian insufficiency.⁵³⁴ This latter recognition during routine obstetric care often serves as an alert to check fragile X syndrome carrier status. We have also seen instances where recognition of carrier status has led to reversal of a putative diagnosis of parkinsonism or early dementia, instead of an actual diagnosis of the fragile X tremor ataxia syndrome manifesting in a grandfather over 60 years of age (see Chapter 16).

      Carrier status for women with a family history of hemophilia A or B cannot be excluded by a normal activated partial thromboplastin time or normal factor VIII or factor IX levels.⁵³⁵ A definitive molecular diagnosis combined with linkage analysis where necessary is needed, especially if prenatal or preimplantation diagnosis is sought. Determination of a pathogenic variant in the structurally complex factor VIII gene enables confirmation of carrier status.^{536, 537} Prenatal diagnosis requests for hemophilia A are uncommon, but have been provided.^538–540 Preimplantation genetic testing (see Chapter 2) for hemophilia has also been accomplished.⁵⁴¹ Noninvasive prenatal diagnosis of hemophilia A and B in hemophilia carriers using maternal plasma and factor VIII and factor IX sequence variants has been demonstrated⁵⁴² (see Chapter 8).

      We all carry a host of deleterious recessive genes (∼100–300)⁵⁴³ and technical advances have enabled routine simultaneous testing of hundreds of autosomal recessive and X‐linked disorders which affect about 1 in 300 pregnancies.⁵⁴⁴ Not well understood by patients is the fact that expanded carrier testing^545–555 examines only a few common mutations in each gene analyzed. The net effect is a significant reduction in the risk of being a carrier of the gene tested. Unfortunately, the refrain heard from patients having had expanded carrier testing is “I am not a carrier.” Financial constraints prevent many couples benefitting from the extensive panel of carrier tests, leaving them with the previously required indications of ethnicity, affected offspring, or family history. This type of limited carrier testing, which includes CF and spinal muscular atrophy, misses about 70 percent of carriers of rare disorders.⁵⁵⁶ For the most part carriers of autosomal recessive disorders are asymptomatic. An important exception are the carriers of the sickle cell disease gene mutation p.Glu6‐Val in the β‐globin chain of hemoglobin, who have an increased risk of both venous thromboembolism and chronic renal disease.⁵⁵⁷ This is an important realization that should lead to care and surveillance, given that about 300 million worldwide have the sickle cell trait.

      Autosomal recessive disease severity when due to compound heterozygous pathogenic variants will be a consequence of the variable expression of the two alleles (e.g. CF with the p.Phe508del and the p.Arg117His alleles resulting only in CBAVD) (see Chapter 15). Gene modifiers too will affect the phenotype. Variant interpretation remains a challenge as well as increasing the need and time taken for genetic counseling given that over 1,800 autosomal recessive genes are known.⁵⁴³

      Clearly, the purpose of expanded carrier screening (see Chapter 14) for healthy couples enables them to benefit from available options that include preimplantation genetic testing, routine prenatal diagnosis, adoption, donor sperm or ova, or surrogacy. This approach has proved acceptable to the American College of Obstetricians and Gynecologists, the American College of Medical Genetics and Genomics, the Society for Maternal‐Fetal Medicine, and the National Society of Genetic Counselors.^{558, 559} The clinical utility and efficacy has been clearly demonstrated.^{546, 549, 551, 558}

Johansen Taber et al.⁵⁶⁰ reported on the actions and reproductive outcomes of 391 at‐risk couples from a tested population of over 270,000 using a panel of 176 genetic disorders. Over 75 percent who had preconception testing, planned or acted to avoid having an affected progeny. More than