Genetics for Nurses in Adult Disciplines

Genetics for Nurses in Adult Disciplines A guide to recognition and referral of congenital and genetic disorders AUTHORS: Golder N. Wilson MD PhD,1 Vijay Tonk PhD,2 REVIEWERS: Shirley Karr BSN RN,3 Joanna K. Spahis BSN CNS,4 Shirley Myers,5 RNC, MSN, FNP, and Sherry Letalian RN6 1Clinical Professor of Pediatrics, Texas Tech University Health Science Center at Lubbock and Private Practitioner, KinderGenome Genetics, Dallas Texas; 2Professor of Pediatrics and Obstetrics-Gynecology; Director, Cytogenetics Laboratory, Texas Tech University Health Science Center at Lubbock;3Genetics Coordinator, Maternal-Fetal Medicine and Genetics, Texas Tech University Health Sciences Center at Amarillo;4Pediatric Clinical Nurse Specialist in Genetics and Coordinator of the Down Syndrome Clinic, Department of Genetics, Children’s Medical Center of Dallas5Women’s Health Nurse Practitioner, Maternal-Fetal Medicine and Genetics, Texas Tech University Health Sciences Center at Amarillo;6Pediatric Clinic Coordinator, Department of Pediatrics, Texas Tech University Health Sciences Center, Lubbock Acknowledgement: This presentation was designed as part of the GEN-ARM (Genetics Education Network for Nursing Assessment, Recognition, and Management) for the Mountain States Region Genetics Collaborative (MSRGCC); contact www.mostgene.org or Ms. Joyce Hooker at joycehooker@mostgene.org

Genetic Disorders are Common Genetic diseases affect 5-10% of children Nurses can recognize and refer genetic disorders without need for esoteric genetic knowledge We will now present cases where your nursing skills and alertness (REYDAR=Recognize, EYDentify, Assess, Refer) can greatly benefit children with genetic diseases. These cases will introduce you to simple principles of genetics that will give you confidence in recognizing these patients and foster a medical home These cases and principles are geared to the nursing genetics primer and resources on the GENARM CD

Think genetics when something is unusual or extreme • Case A: A term AGA newborn product of a pregnancy with little prenatal care has an enlarged and distorted head, blue-gray sclerae (whites of the eyes), and deformed limbs. X-rays show multiple fractures, and the mother blames this on an auto accident at 7 months gestation. Do you agree? Newborn with large head and deformed bones with fractures by x-ray

This unusual presentation should prompt REYDAR for a genetic disease • More detailed family history would be useful, although many genetic disorders occur as new changes (new mutations) • The symptoms of blue sclerae and multiple fractures could be searched on the website Online Mendelian Inheritance in Man (go to http://www.ncbi.nlm.nih.gov/entrez/ or enter OMIM in search engine). They point to a disorder called osteogenesis imperfecta (166210 • OMIM contains >6000 diseases that can be searched by symptom, name, or number; associated databases contain genetic education, medical literature (PubMed), and even the complete human genome sequence/gene map. • Also useful is the companion database www.genetests.org that lists testing (when available) for the particular genetic disease (go to the clinical laboratory section and search by disease name

The family history indicated that the mother and other relatives had mild features of osteogenesis imperfecta or brittle bone disease (see Chapter 2) Suspicion of genetic disease underlying this unusual infant led to referral and genetic counseling for this autosomal dominant disease—mother’s guilt about her accident was assuaged and she learned she had a 50% chance each of her future children would have OI Family history Pedigree

Case example 1: Nurses in adult disciplines might have identified the mother or maternal relatives with OI, giving them the advantages of genetic counseling for a 50% recurrence risk and potential therapy with pamidronate that can decrease the risk for fractures

Think genetics when something is unusual or extreme • Case example 2: A school physical • A 14-year-old male is seen for a routine school physical and asks clearance to participate in sports. His mother mentions he has had surgery for fused sutures (craniosynostosis) including reconstruction of his nasal bridge. He has also had a history of mild mental disability, and the school nurse notices long fingers and a concave chest, prompting recall about Marfan syndrome and heart disease. The nurse decides to postpone approval for sports participation and refers the young man for genetic evaluation. Do you agree?

In case example 2, the recollection of Marfan syndrome (154700) was appropriate because of the boy’s long “spider” fingers (arachnodactyly). Echocardiographic studies would show a dilated aorta and he should certainly not participate in collision or high-intensity sports. Genetics referral would establish that this child had a disorder called Shprintzen-Goldberg syndrome (118212) that was similar to Marfan but different in having craniosynostosis and mental disability. Shprintzen-Goldberg syndrome is also autosomal dominant, meaning that the boy’s normal parents would have a minimal recurrence risk for future affected children and the boy himself would have a 50% chance to transmit the condition with each future pregnancy. Preventive management in his case allowed protection from harmful activities and access to medications such as propranolal or Losartan that may be helpful in treating aortic aneurysms.

Case example 2: Recognition of a genetic condition and preventive management for this teenager allowed protection from harmful activities and access to medications such as propranolal or Losartan that may be helpful in treating aortic aneurysms. A family with Marfan syndrome is discussed in chapter 2, showing the advantages of recognizing this disease with its risks for heart and eye complications.

Note that simple recognition and assessment of possible genetic disease, not sophisticated knowledge, optimized nursing care of for the example families. • Nurses with additional interest in genetics can learn to construct pedigrees, interpret inheritance mechanisms, and provide recurrence risks for the parents (genetic counseling) • Nurses are ideally positioned to be genetic counselors with their hands-on contact, emphasis on education, and focus on prevention • Read chapters 2-4 in the primer to acquire the skills for genetic counseling

Genetic disease can be defined by abnormal genes, tissues, or chromosomes (genetic testing) Categories of genetic disease relate to the steps from gene to family (genetic hierarchy) • A family has people with unusual symptoms • A person has abnormal form or function (disease) • A tissue (cell to organ) has abnormal structure (metabolic disorders) • A chromosome is extra or missing (chromosome disorders) • Several genes (plus environment) are abnormal (multifactorial disorders or susceptibilities) • A gene (DNA to RNA to protein) is abnormal (Mendelian disorders

Categories of genetic or congenital disease

Mendelian diseases like osteogenesis imperfecta have distinctive family patterns • The pattern of affected relatives is caused by transmission of single genes, each with a unique position (locus) on the chromosome. • The paired chromosomes 1-22 and XX in females imply paired genes except for X and Y genes in the male • Dominant or recessive diseases result when one or both gene partners (alleles) are abnormal. • Abnormal alleles can be predicted (genetic risks) and sometimes diagnosed through their abnormal DNA sequence or RNA/protein expression.

Sickle cell anemia is recessive, requiring both β-globin alleles to be abnormal (SS versus AS trait or AA normal). Sickle cell anemia can be predicted (25% risk for next child) and tested (abnormal S protein or gene) Other inherited anemias can be related to different abnormal globin alleles (C, D, E, thassemias). A or S

OI is caused by one abnormal allele at a collagen gene (genotype Oo) • Different phenotypes of OI relate to different collagen alleles • The >6000 Mendelian diseases thus relate to a similar number of different genes and abnormal alleles. • Characterization of abnormal alleles provides DNA testing—few of the >1600 characterized disease genes are available to the clinic. • Simultaneous analysis of multiple genes (DNA chips, arrays) is not yet practical in the way that karyotypes define any abnormal chromosomes

Know categories, not rare diseases • Single genes altering development cause birth defects and syndromes • Single genes altering enzyme pathways cause inborn errors of metabolism • Single genes altering organ function(s) produce extreme or early–onset • examples of common disease (e.g., neonatal diabetes) Mendelian diseases reflect transmission of single genes (abnormal alleles) = DNA diagnosis Multifactorial diseases reflect multiple abnormal genes plus environment = DNA/HLA markers Many genes altering development cause isolated birth defects like cleft palate Many genes altering enzyme pathways cause common metabolic diseases (e.g., adult-onset diabetes, hyperlipidemia) Many genes altering organ function(s) produce adult diseases (e.g., schizophrenia) Chromosomal diseases imbalance multiple genes and cause multiple birth defects = Karyotype

REYDAR of common adult presentations Recognition → Category → Referral ↔ Medical home • Case 10P—Diabetic woman who becomes pregnant • Case 11P—A pregnant couple and cystic fibrosis screening • Case 12P—A pregnant couple with infertility and two miscarriages • Case 13P—Couple with maternal history of mental retardation (see Chapter 1)

Case 10P. Diabetic woman who is 10 weeks pregnant • A 25-year-old woman with juvenile diabetes has been managed by her family practitioner for several years. She calls and asks for referral to obstetrics because she is approximately 6 weeks pregnant. She has had several hospitalizations for diabetic control and states that her blood sugars have been high for the past few weeks. The obstetric nurse discusses the risks of hypoglycemia, respiratory distress, and polycythemia for infants of poorly controlled diabetic mothers, but does not mention another risk for the fetus, which is?

Women with poorly controlled diabetes have a 3-5 fold increased risk for congenital anomalies in their fetus that can be remembered by 3Cs—cranial, cardiac, and caudal anomalies. Cranial defects can include anencephaly as in case 9P or holoprosencephaly (photo at right); caudal defects underdevelopment of the sacrum/lower limbs (caudal regression) or spina bifida. Anomaly patterns like the VATER association (192350) or Goldenhar syndrome (164210) also occur at higher frequency in infants of diabetic mothers.

Preconception counsel • Stringent diabetic control in later pregnancy can eliminate neonatal physiologic changes like hypoglycemia, hypocalcemia, polycythemia, and respiratory problems. Lowering the risks of diabetic pregnancy illustrates the potential collaboration of pediatric or adult and obstetric nurses in preconception counsel. Nurses in adult disciplines can recognize women or couples with increased pregnancy risks and refer them for pregnancy planning.

Case 14P: Man whose father had heart attack at age 41 (hypercholesterolemia) A nurse practitioner in a family practice clinic performs a routine physical on a man of 35 for insurance purposes. He notes on his preassessment form mention of the man’s father who died of a heart attack at age 41. He completes a more detailed family history indicating that the man has two older brothers and two younger sisters, and that one of the older brothers has had two heart attacks and bypass surgery at age 45. The man’s father was adopted, and his mother is in good health with no heart disease in her family. What concerns should be raised?

Case 14P: Discussion • Besides revealing patterns of disease suggestive of Mendelian inheritance, a family history can reveal susceptibilities or risk factors that lead to screening preventive strategies. Common disorders like isolated birth defects, coronary artery disease, diabetes mellitus, or hypertension follow a model of multifactorial determination. This model implies the interaction of multiple genes with the environment and a threshold above which susceptibility becomes disease. A growing number of laboratory tests are being devised to measure individual gene effects that combine with other genetic and environmental factors to produce disease. Coronary artery disease follows the multifactorial model and is associated with several genetic and environmental risk factors—blood lipid or homocystine levels, obesity, hypertension, diabetes, and certain clotting factors.

Case 14P: Discussion • A family member with extreme or unusual presentation of a common disease (e.g., young age or multivessel obstruction in coronary artery disease) indicates increased susceptibility to that disease (lower threshold) that may be transmitted to offspring. The man’s father with an early onset coronary gives him a higher risk (3-5%) to develop coronary artery disease and justifies laboratory testing for the disease (e.g. stress test for early coronary occlusion) or factors (e.g., blood pressure, blood sugar-cholesterol-lipoprotein-homocysteine-clotting factor abnormalities) that predispose to disease.

Case 14P: Discussion • Abnormal laboratory findings can lead to medical (statins, heparin) or dietary (low cholesterol, folic acid) therapies and improved outcome when the hereditary risks are recognized. Among the several genes interacting to cause multifactorial diseases may be occasional ones of major effect—such was the case for the low-density lipoprotein receptor where mutations caused very high cholesterol in the dominant condition familial hypercholesterolemia ( 144010). Extreme or unusual presentations of common diseases may also point to Mendelian disorders as well as to predisposing risk factors. The Surgeon General has recommended that all individuals know their family histories, an obligation that nurses of all disciplines can greatly assist.

Review of genetic testing • Mendelian disorders—DNA tests for specific mutant alleles. LIMITATION: Only a few diseases are sufficiently common that DNA testing is commercially feasible • Chromosome disorders—routine karyotypes on blood, amniocytes, bone marrow or solid tumors; FISH testing for subtle changes. LIMITATION: Chromosome testing cannot analyze component genes • Multifactorial disorders—DNA tests for associated DNA variants (DNA markers) that indicate susceptibility to disease. LIMITATION: DNA marker testing is still in the research stage

Single gene (Mendelian disorders) that are sufficiently common can be diagnosed by DNA testing for changes in gene sequence or structure; the man with family history of heart attacks (case 14) could have blood cholesterol studies and DNA testing for mutations in the LDL receptor Diagram of gene and its encoded LDL receptor protein that imports cholesterol into cells—the position of mutation (shown below gene) determine the severity of hypercholesterolemia

Chromosome disorders can be diagnosed by a routine karyotype, performed on cells from individuals (blood) or fetuses (blood by fetoscopy, dividing villus cells from chorionic villus sampling, amniotic fibroblasts from amniotic fluid). This testing requires at least 5-7 days for results.

13 18 21 X Y Cloned DNA segment from target chromosome FISH probes Fluorescent label 13, X, Y No culture or need for metaphase spreads 18 21 Male with trisomy 13 Now a rapid FISH test is available that does not require stimulation of cell division and gives results within 2-4 hours. Rapid FISH highlights chromosomes commonly involved in disorders—e.g., 13 (Patau syndrome), 18 (Edwards syndrome), or 21 (Down syndrome), showing three versus the normal two FISH signals in each cell nucleus (X and Y probes also show Turner syndrome ordocument sex in cases of ambiguous genitalia)

Chromosome disorders • Miscarriages (50-60%), liveborn children (0.5%), cancer tissue (many have diagnostic changes)--over 200 chromosomal diseases due to extra or missing chromosome or parts of chromosomes (p small or q long arms) • Hallmarks are multiple major or minor anomalies (unusual appearance) with mental disability • Most recognized by a routine karyotype, but FISH is required to detect submicroscopic deletions (e.g., DiGeorge) or the 3% of suspect children who have changes on subtelomere FISH after normal karyotypes • Individual submicroscopic deletions are found in Williams (7q), hereditary retinoblastoma (13q), Prader-Willi (15q), Shprintzen-DiGeorge spectrum (22q), and ~15 others. • Consider chromosomes in any child with unexplained mental disability and/or multiple birth defects, couples with >2 miscarriages, prenatal diagnosis for women over age 35 • Prenatal diagnosis of chromosome disorders can be performed by preimplantation diagnosis (first week), chorionic villus sampling (10-12 weeks), or amniocentesis (15-18 weeks). See Chapter 7 for more information

Multifactorial Disorders Table 4.1. Multifactorial Disorders in the United States *Ranks first for neonatal causes of death; approximate scale: ++++ (100% of predisposition due to genetic factors as for Mendelian disorders) to + (20% of predisposition due to genetic factors)

Multifactorial Disorders • Most isolated birth defects like cleft palate, hypospadias, heart defects, spina bifida • Many common diseases like diabetes mellitus, hypertension, mental illness, mild mental/learning disabilities • Multiple genes involved, giving lower transmission risks (about 3% for offspring of affected parent, sibling to affected child) • Therapeutic goals are to manipulate environment (e.g., folic acid) either generally or for specific high-risk individuals identified by associated DNA markers (more diverse and sensitive than HLA haplotypes

Multifactorial disorders: For some (e.g., coronary artery disease), single genes of major effect (e.g., those regulating cholesterol) are good risk markers) Recognizing at-risk children or adolescent females provides important opportunities for nursing education and prevention (see chapter 4)

Case 14P: Discussion • A major initiative of modern genetics is to expand recognition of disease susceptibilities by examining variable regions of DNA. The human genome project revealed a difference in DNA sequence for unrelated individuals every 1 in 200 to 500 nucleotides, implying at least a million DNA differences per person. Most of these are single base pair differences that do not lead to clinical differences—single nucleotide polymorphisms (SNPs). DNA markers that travel with disorders like schizophrenia (OMIM #181500) or Alzheimer disease (OMIM #104300, others) potentially allow measurement of individual susceptibility in the way that cholesterol conveys risk for coronary artery disease. With further study, DNA markers may provide tests for susceptibility and even prevention through modified expression of their associated genes.

Case 15P: Woman whose mother and grandmother had breast cancer at young ages. • An obstetric nurse assesses a woman aged 37 who is about 6 weeks along in her current pregnancy. The woman has two prior children and has no chronic illnesses; her husband is age 40 with a benign family history. The nurse ascertains that the woman has two sisters, aged 35 and 32, each with two children and no health problems. The woman’s mother is a breast cancer survivor, having her first cancer at age 31. Her mother’s mother also had early breast cancer at age 36, dying by age 45. Her mother has two sisters, one of whom died from ovarian cancer at age 47 and another who has had cautery for cancer in situ of the cervix. What information should the nurse provide to this couple?

Case 15P: Discussion Besides recognition of “advanced” maternal age with discussion of increased risks for chromosome abnormalities, the nurse should address increased susceptibility to breast and ovarian cancer. Although not necessarily pertinent to the current pregnancy, the woman has increased risks for breast cancer and should know about options for breast cancer gene testing. Mutations in the breast cancer genes BRCA1 (OMIM #113705) and BRCA2 (OMIM #600185) account for about 10% of breast cancer, characterized by its early onset and association with ovarian cancer. Testing would ideally be performed on one of the woman’s affected relatives, ascertaining the presence of BRCA mutations versus usually multifactorial breast cancer. If positive, the woman should be informed about her 50% risk to transmit the mutation to each child.

Case 15P: Discussion • Cancers are additional examples of multifactorial disorders like coronary artery disease that were discussed in the previous section. Most will confer low risks for family members unless the same cancer is present in multiple relatives or a given cancer has an unusual or extreme presentation (e.g., early onset, associated features). Single gene diseases can also be concealed amidst multifactorial cancers, exemplified by the BRCA genes or cancer syndromes like Li-Fraumeni (bone, breast, brain cancers—OMIM #151623) or Gardner disease (colon cancer-- OMIM #175100) that are due to single gene mutations. Alertness for early onset or recurrent types of cancers in families allows evaluation for a growing number of cancer genes or susceptibility markers.

Rules from Chapter 1 • RULE : Recognition of family histories with multiple affected individuals or those with unusual/extreme presentations of common diseases (e.g., heart attacks) allows definition of risk factors (e.g., cholesterol) and preventive management.

. Case 13P: Couple with maternal history of mental retardation Bob and June present to a nurse practitioner for prenatal care at an estimated 6 weeks of pregnancy. Bob is 26, June 24, and they had a normal daughter Karen two years ago with no pregnancy or delivery problems. Both are healthy and of Caucasian ancestry, and Bob’s family history is normal The nurse finds that June is an only child, but that her mother Gail has two brothers who have mental retardation. In addition, Gail has a sister Joan with with two boys and a girl, and one boy Eric has mental retardation thought due to birth injury. Gail’s other sister Jill has three boys and two girls, and her eldest son Jim has mental retardation of unknown cause. One of Jill’s daughters has also had learning problems that caused her to drop out of high school, and she has a preschool son Bert with speech delay. What concerns should the nurse address?

Gail Joan Jill June Case 13P: Discussion Besides the usual options for genetic and fetal screening (ultrasound, quad screen, cystic fibrosis screening), the nurse should recognize the positive family history and recommend genetic evaluation. The presence of several relatives with the same condition (mental disability) brings up the possibility of Mendelian disease, and sketching of the family pedigree (below) would suggest an X-linked disorder associated with mental retardation. Genetic evaluation would inform June that her mother Gail has a 50% chance and she a 25% chance to be a carrier for the X-linked disease.

Case 13P: Discussion The X-linked fragile X syndrome (OMIM #300624) is the most common genetic cause of mental disability with an estimated incidence of 1 in 2000 males. Since June is early in her pregnancy, a fragile X DNA test could be performed on one of her male relatives to confirm or exclude this diagnosis. It would be ideal if one of her affected male relatives could be evaluated by a clinical geneticist so that the diagnosis of fragile X syndrome or another of the >20 syndromes associated with X-linked mental disability could be suspected.

If the diagnosis of fragile X were confirmed in a male relative, June could have fragile X DNA testing to determine if she was a carrier. If her relatives were not available, or if their evaluation could not be accomplished in a time frame to accomplish June’s testing and options for prenatal diagnosis, then June could have the fragile X DNA test but realize that a negative result would not exclude other X-linked mental retardation syndromes. Preconception knowledge of fragile X syndrome in her family with recognition of her carrier status would have allowed Jill and Bob to consider other options such as surrogate egg donor or in vitro fertilization with preimplantation genetic diagnosis (PGD) and implantation of an unaffected embryo. Their case emphasizes the value of recognizing suspect family histories as early as possible in order to provide genetic counseling and reproductive options.

Common disorders (like mild mental or learning disabilities often exhibit multifactorial determination • Case 13P: Discussion • If Jill or Bob had only one relative with mental disability with no obvious pedigree pattern, then multifactorial determination of the mental disability would be most likely. The odds of multifactorial disability would be increased if the affected person was mild and did not have an unusual appearance or biochemical abnormalities. Multifactorial disorders confer a 2-3% risk for primary relatives—i.e., siblings/parents/children. Since Jill and Bob had normal intellect, their risks from one relative with mental disability would be less than 2-3%.

Review Questions 11. A woman is diagnosed with Crohn’s disease, and wishes to know the risk that her daughter will develop the disease. She is otherwise normal with an unremarkable family history. The likely inheritance mechanism and her daughter’s risk would be: • Autosomal dominant with a 50% risk • Autosomal recessive with a 25% risk • X-linked recessive with a 25% risk • Chromosomal with a 10-15% risk • Multifactorial determination with a 5-7% risk

12. A 24-year-old Ashkenazi Jewish woman develops bilateral breast cancer. Her mother and grandmother died of ovarian cancer, and a maternal aunt also had early onset breast cancer. She has two daughters aged 12 and 16. The most probable mechanism and risk to her daughters would be: • Multifactorial determination with a 1-2% risk • Autosomal dominant with a 50% risk • Autosomal dominant with a 25% risk • X-linked dominant with a 50% risk • X-linked dominant with a 25% risk

13. A male teenager presents for a school physical with tall stature, thin body build, concave chest (pectus), long fingers, flat feet, and increased joint laxity. His father died at age 35 with a heart attack. He wants approval to play basketball. An important disease category and disorder to consider would be: • Coronary artery disease and myocardial infarction • Coronary artery disease and congestive heart failure • Connective tissue disease and aortic dilatation • Connective tissue disease and myocardial infarction • Connective tissue disease and aortic coarctation

14. A 30-year-old man has hypertension controlled by diet and medication, and one of his three siblings is affected. His father died of kidney failure, and one of the man’s three sons had urinary tract infections with cystic kidneys on ultrasound. The most likely diagnosis is: • Multifactorial predisposition to renal failure • Isolated congenital anomaly of the urinary tract • Autosomal dominant polycystic kidney disease • Autosomal recessive polycystic kidney disease • X-linked recessive polycystic kidney disease

Answer 1E • 1. Crohn’s disease is a multifactorial disorder with a 7.5% risk for siblings of affected individuals to develop the disease (see Chapters 4 and 12). Approximately the same risk would apply to other primary relatives such as the woman’s daughter.

Answer 12B • 12. The early onset and family history of cancer is suggestive of Mendelian disease (e.g., BRCA—113705--or Li-Fraumeni syndrome—112480--gene mutations, see chapter 12). The daughters would be at 50% risk for breast cancer, and DNA testing on the mother could determine if a particular BRCA1, BRCA2, or p53 (Li-Fraumeni) tumor suppressor gene were present. BRCA mutations are more common in Ashkenazi Jews. The BRCA genes account for about 10% of breast cancer, the rest being multifactorial. Thus, negative DNA tests do not eliminate the need for annual screening. Testing of the minor daughters would raise the ethical issues of informed consent and autonomy (parent versus child), but would probably be pursued because of the advantages of early screening or prophylactic mastectomy.

Answer 13C • 13. The physical findings are characteristic of diseases with loose connective tissue, and the father-son affliction most suggestive of autosomal dominant diseases like Marfan syndrome (154700). These individuals are at risk for aortic dissection and sudden death and should not participate in collision or high intensity sports. Note that the history of “heart attack” in the father was probably an aortic dissection, stressing the need for medical and autopsy information to discriminate among cardiac causes of sudden death (see Chapter 12).

Answer 14C • 14. The family history and presence of hypertension is suggestive of an autosomal dominant renal disorder, and the dominant form of polycystic kidney disease (173900) could be found in OMIM. This disease may be silent, causing severe hypertension and presenting with strokes at an early age. Early diagnosis in at-risk individuals (this man was at 50% risk) is important for treatment of hypertension. The 30-year-old man should have imaging studies to confirm the diagnosis followed by imaging studies of his two apparently normal sons and siblings.

Genetics for Nurses in Adult Disciplines