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 |
