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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 50 percent of at‐risk couples terminated pregnancies. Relying on a survey study, the authors acknowledge, has limitations so far as memory, response bias, and selection (infertility problems) are concerned. In a smaller study, others⁵⁴⁹ demonstrated the clear superiority of expanded carrier screening compared with ethnicity‐based testing, with over threefold detection. Punj et al. offered preconception next‐generation sequencing to determine carriers and found 12/71 couples at risk.⁵⁴⁸ Eight were carriers of hemochromatosis. These authors analyzed 728 genes in 202 individuals, 78 percent being determined to have at least one positive carrier result. In this exploratory study, which used a 148 gene‐panel rather than the ACMG actionable panel of 59 genes, 3.5 percent of participants had a medically actionable variant⁵⁴⁸ (see Chapter 14). Applying their analysis to the ACMG panel, 2.9 percent had an actionable variant.

Ethnicity‐based carrier testing (Table 1.5) remains the only option for large swaths of the world's population. Selective Ashkenazi Jewish mutation carrier testing, for example, for disorders listed in Table 1.5 do provide valuable but limited information, leading to options noted above. A study of 6,805 Jewish patients (Ashkenazi, Sephardi, and Mizrahi) having expanded carrier screening showed that 64.6 percent were identified as a carrier of one or more of 96 disorders⁵⁶² (Table 1.6). The authors noted that >80 percent of the reported variants would have been missed by standard Ashkenazi Jewish screening protocols. One in 16 couples were identified as joint carriers with a 25 percent risk of having an affected child. A novel, likely pathogenic variant was seen in about 2.5 percent of patients tested. A whole‐exome sequencing study of 123,136 cases examined carrier rates in six ethnic groups, focusing on 415 genes associated with severe recessive disorders.⁵⁶³ These authors found that 32.6 percent (East Asian) and 62.9 percent (Ashkenazi Jewish) were variant carriers of at least one of the 415 genes. A pan‐ethnic screen using these 415 genes would identify up to 2.52 percent of at‐risk couples.

Table 1.5 Genetic disorders in various ethnic groups.

Ethnic group	Genetic disorder
Africans (black)	Sickle cell disease and other disorders of hemoglobin α‐ and β‐thalassemia Glucose‐6‐phosphate dehydrogenase deficiency Benign familial leucopenia High blood pressure (in females)
Afrikaners (white South Africans)	Variegate porphyria Fanconi anemia
American Indians (of British Columbia)	Cleft lip or palate (or both)
Amish/Mennonites	Ellis–Van Creveld syndrome Pyruvate kinase deficiency Hemophilia B
Armenians	Familial Mediterranean fever
Ashkenazi Jews	A‐β‐lipoproteinemia Bloom syndrome Breast cancer Canavan disease Colon cancer Congenital adrenal hyperplasia Dysferlinopathy (limb girdle muscular dystrophy 2B) Dystonia musculorum deformans Factor XI (PTA) deficiency Familial dysautonomia Familial hyperinsulinism Fanconi anemia (type C) Galactosemia Gaucher disease (adult form) Iminoglycinuria Joubert syndrome Maple syrup urine disease Meckel syndrome Niemann–Pick disease Pentosuria Retinitis pigmentosa 590 Tay–Sachs disease Warsaw Breakage syndrome 561
Chinese	Thalassemia (α) Glucose‐6‐phosphate dehydrogenase deficiency (Chinese type) Adult lactase deficiency
Eskimos	E1 pseudocholinesterase deficiency Congenital adrenal hyperplasia
Finns	Aspartylglucosaminuria Congenital nephrosis
French Canadians	Neural tube defects Tay–Sachs disease
Irish	Neural tube defects Phenylketonuria Schizophrenia
Italians (northern)	Fucosidosis
Japanese and Koreans	Acatalasia Dyschromatosis universalis hereditaria Oguchi disease
Maori (Polynesians)	Clubfoot
Mediterranean peoples (Italians,	Familial Mediterranean fever
Greeks, Sephardic Jews, Armenians, Turks, Spaniards, Cypriots)	Glucose‐6‐phosphate dehydrogenase deficiency (Mediterranean type)
	Glycogen storage disease (type III)
	Thalassemia (mainly β)
Norwegians	Cholestasis‐lymphedema
	Phenylketonuria
Yugoslavs (of the Istrian Peninsula)	Schizophrenia

Table 1.6 Residual risk values for diseases in Ashkenazi Jewish populations.

Disease	100% Ashkenazi Jewish carrier frequency	Detectability	Residual risk	Probability of affected fetus if parents pos/nega
Gaucher disease	1 in 15	0.95	1 in 281	1 in 1,124
Cystic fibrosis	1 in 23	0.94	1 in 368	1 in 1,472
Tay–Sachs disease	1 in 27	0.98	1 in 1,301	1 in 5,204
Familial dysautonomia	1 in 31	>0.99	1 in 3,001	1 in 12,004
Canavan disease	1 in 55	>0.97	1 in 1,801	1 in 7,204
Glycogen storage disease type 1a	1 in 64	0.95	1 in 1,261	1 in 5,044
Hyperinsulinemic hypoglycemia	1 in 68	0.90	1 in 671	1 in 2,684
Mucolipidosis IV	1 in 89	0.95	1 in 1,761	1 in 7,044
Maple syrup urine disease	1 in 97	0.95	1 in 1,921	1 in 7,684
Fanconi anemia	1 in 100	0.99	1 in 9,901	1 in 39,604
Dihydrolipoamide dehydrogenase deficiency	1 in 107	>0.95	1 in 2,121	1 in 8,484
Niemann–Pick disease type A	1 in 115	0.97	1 in 3,801	1 in 15,204
Usher syndrome type 3	1 in 120	>0.95	1 in 2,381	1 in 9,524
Bloom syndrome	1 in 134	0.99	1 in 13,301	1 in 53,204
Usher syndrome type 1F	1 in 147	≥0.75	1 in 585	1 in 2,340
Nemaline myopathy	1 in 168	>0.95	1 in 3,341	1 in 13,364

^a One parent is positive and one parent is negative by carrier screening.

Source: Modified from Scott et al.⁵⁶⁴

However, the limitations of ethnic‐based carrier testing were revealed by a genetic ancestry analysis of >93,000 individuals having expanded carrier testing using a 96‐gene panel.⁵⁶⁵ Nine percent of those tested had an ancestry from a lineage inconsistent with self‐reported ethnicity.

Multiple published reports on preconception or prenatal expanded carrier screening using large but variable‐sized gene panels overwhelmingly support this approach above ethnicity‐based testing.^{545, 549, 566–572}

Although not currently required in preconception carrier screening, testing for hereditary cancer risk should be considered. A personal or family history of cancer as well as ethnicity currently serves as an indication for screening. Autosomal dominant disorders are otherwise not usually subject to screening. In a study of 26,906 individuals in the Healthy Nevada Project screened for BRCA‐related breast and ovarian cancer, Lynch syndrome, and familial hypercholesterolemia, 1.33 percent were found to be carriers of pathogenic or likely pathogenic variants.⁵⁷³ Moreover 90 percent of carriers had not been identified previously, and only 25.2 percent had a relevant family history. These three disorders determined by screening (not family history) are not usually considered for prenatal diagnosis or preimplantation genetic testing. However, other autosomal dominant disorders with manifestations in childhood (e.g. multiple endocrine neoplasia type 2B, familial adenomatous polyposis, long QT syndrome, cardiomyopathy) do qualify for preconception, preimplantation, and prenatal testing. A study of 23,179 individuals with a family history of cancer had next‐generation sequencing using a 30‐gene panel.⁵⁷⁴ A total of 2,811 pathogenic variants were found in 2,698 individuals for an overall pathogenic frequency of 11.6 percent. For those of Ashkenazi Jewish descent three‐quarters of the pathogenic variants in the BRCA1 and BRCA2 genes would have been missed if only the routine three common founder mutations were tested.

Geneticists and genetic counselors will attest to the frequent challenges they encounter faced by their patients' difficulty comprehending genetic test results, implications, and options. On the heels of the technologic advances in genetics have come commercialization in the form of direct‐to‐consumer (DTC) testing. Few patients are cognizant of the commercialization realities that include selling of their data, receiving misleading results, being faced with incorrect, false‐positive or false‐negative results, a lack of informed consent, confidentiality, and privacy.^575–580 There is a wide spectrum of laws that govern genetic testing in most countries, with special reference to laboratory accreditation, staff certification, genetic counseling requirements, and informed consent.

In one study of identical twins there was a lack of concordance between laboratories.⁵⁸¹ In an illustrative case, the result provided was actionable, but no action was taken by the recipient of the DTC communication.⁵⁸² Ethical breaches, including testing of children, further complicate DTC practices.⁵⁸³

Professional organizations, aware of all these issues, have discouraged the use of DTC genetic testing. Position statements have accordingly been issued by the American College of Obstetricians and Gynecologists,⁵⁸⁴ the American College of Medical Genetics and Genomics,⁵⁸⁵ the Joint Society of Obstetricians and Gynecologists, and the Canadian College of Medical Genetics.⁵⁸⁶ A range of laws exist in Europe, with France and Germany banning DTC genetic testing.⁵⁸⁷ Serious concern has been expressed about the ethical, legal, and regulatory challenges of DTC testing in Ireland⁵⁸⁸ and Europe.⁵⁸⁹