Genetics

Denice Gardner, MSN, NNP-BC

Objectives

Discuss genetics and its affects on the newborn

Genetics

• Pictures included in presentation were obtained from the Mosby’s Nursing Consult web site

• Graphics used in presentation were created by the author

Terminology

Genetics- study of heredity Chromosome- structural element in a cell

that contains the genes and all the genetic information; human cells have 23 pairs of chromosomes

DNA- double-stranded nucleotide that carries genetic material

Gene- segments of the DNA that are responsible for inherited traits; contain the “blueprint for everything that will make “you”

Terminology

Allele- variations in a gene; segregates during meiosis; receive only one pair from each parent; only 2 alleles can be present in one person

Autosome- one of the 22 chromosomes that do NOT determine the sex of a person

Sex chromosome- the X & Y chromosome that determines the sex of a person

Terminology

Gamete- one of the 2 cells that joins together during sexual reproduction to create a new being

Genotype- genetic make-up of a personPhenotype- biochemical, physiologic, &

morphologic characteristics of a person (hair color, skin type, etc.) & is determined by his/her genotype and environment

Terminology

Haploid- number of chromosomes in a gamete; half the number of chromosomes in a person, 23 chromosomes

Diploid- contains a set of maternal & paternal chromosomes to equal 46 total chromosomes

Locus- location of the gene in the chromosome

Penetrance- degree to which an inherited trait will be expressed in a person

Dominant & Recessive Genes

Dominant- expressed & transmitted even if only ONE parent has the gene

Recessive- expressed only when BOTH parents have the gene

Homozygous- two identical alleles for a particular gene (one from each parent)

Heterozygous- two different alleles for a particular gene

Possible Combinations

Both can be dominant (AA)Both can be recessive (aa)One can be dominant & one can be

recessive (Aa)

Autosomal Dominant

Appears in every generation without skipping

Either parent can pass the gene on to their children

Risk for affected individuals to have affected children is 50% with every pregnancy

If 2 affected parents mate, 75% of their children will be affected

Unaffected individuals do NOT have affected children

Trait is found equally in males and females

Autosomal Dominant

Autosomal Recessive

Expressed only when both parents transmits it to their offspring

Alternates generations If 2 affected people mate, all children with

be affected If 2 carriers mate, the risk of having an

affected offspring is 25% If a carrier & an affected person mate, the

risk of having an affected offspring is 50% Risk of an unaffected carrier having a child

who is a carrier is 50% with each pregnancy

Autosomal Recessive

X-Linked Dominant

Female children of affected males are ALL affected

Male children of affected males are unaffected Trait appears in every generation All children of affected females MAY be

affected X-Linked dominant problems affect twice as

many females as males

X-Linked Dominant

X-Linked Recessive

Only Male children are affected. (Female may be affected if mother is a carrier and father is affected)

Traits cannot be transmitted from father to son because the father only contributes the Y chromosome

Transmission of the trait occurs from father to all daughters (who will be carriers)

X-Linked Recessive

Heterozygous females transmit the gene to half of their sons, who will be affected, & to half their daughters, who will be carriers

Transmission is horizontal among males of the same generation & then skips a generation

Carrier females transmit the disorder

X-Linked Recessive

Chromosomal Defects: Abnormal Number

Polyploidy- contains more than 2 sets of chromosomes, showing multiples of the haploid number; usually dies as embryos or fetuses

Nonmultiples- designated by the suffix “-somy”

Monosomy- one less than the diploid number (45 chromosomes)

Trisomy- one more than the haploid number (47 chromosomes)

Chromosome Defects: Abnormal NumberCauses-

Nondisjunction- failure of paired chromosomes to separate during cell division; most common cause of all chromosome disorders

Chromosome lag- failure of a chromosome to travel to the correct daughter cell

Anaphase lag- failure of a chromosome or chromatin to be incorporated into one of the daughter nuclei following cell division as a result of delayed movement during anaphase

Chromosomal Defects: Abnormal Number

Mosaicism:Nondisjunction of an anaphase lag

that occurs during cell division after fertilization

Cells within the same person that have different genetic make-up

Mosaicism:

Chromosomal Defects: Abnormal Structure

Deletion- loss of part of a chromosome Translocations- displacement of part of a

chromosome to an abnormal site, whether on another chromosome or in the wrong position on the same chromosome

Polygenic effects- type of inheritance in which a trait is dependent on many different gene pairs with cumulative effects

Chromosome Defects: Abnormal Structure

Environmental influences- nutrition, drugs, & living environment (radiation, pollution, bacteria, virus) that affect the genetic make-up & developing embryo while in utero

Duplication- duplication of an area of the DNA that contain contains a gene; results in mutations that have no deleterious affects on a person

Chromosomal Defects: Abnormal Structure

Inversion- area of a chromosome breaks off and then reattaches itself in the opposite direction

Nonreciprocal translocation- one-way transfer of genes from one chromosome to another

Chromosomal Defects: Abnormal Structure

Basic GeneralizationsLoss of an entire chromosome is

usually incompatible with lifeOne X chromosome is necessary for

life & developmentIf the Y-chromosome is missing, life &

development may continue but will follow female pathways

Chromosomal Defects: Abnormal Structure

Extra entire chromosomes, translocations of extra chromatin material, & insertion of extra chromatin material are often compatible with life & development

Multiple congenital structural defects are present when gross aberrations are present

Prenatal Testing

Alpha-Fetoprotein Test (AFP)Usually done at 16-18 weeks gestationIs a screening test, not a diagnostic

testIf abnormal, ultrasound should be

obtained

Prenatal Testing

Elevated AFP may indicateGreater gestational age than expectedMultiple gestationRisk of neonatal complications,

including spontaneous abortion, PTL, or IUGR

Fetal structural defects: neural tube, abdominal wall, esophageal or intestinal obstruction, or renal anomalies

Prenatal Testing

Multiple Marker Screen (“Quad Screen”)Measures AFP, hCG, unconjugated

estriol (uE3), & dimeric inhibin-A (DIA)Useful in detecting conditions like

trisomiesUsually done between 15-20 weeks

gestationIf, abnormal, ultrasound should be

obtained

Prenatal TestingUltrasonography- uses high-frequency

sound waves to display sectional planes of the uterine contents on a monitorRecommended by 16-20 weeks of age

for gestational age verification & assessment

Used to detect abnormalities of the fetus, placenta, amniotic fluid, & uterus & to monitor changes in anatomy & growth with serial ultrasounds

Only as good as the person’s training-not just on the equipment

Prenatal Testing

Amniocentesis- removal of amniotic fluid through a needle placed through the abdomen, usually in conjunction with ultrasonography, for the purpose of chromosome analysis & other biochemical testsUsually done between 16-18 weeks

gestationIndications for procedure:

Advanced maternal age (>35yrs at time of delivery)

Previous fetus with a neural tube

Prenatal TestingMore indications for procedure

Both parents known heterozygous carriers of autosomal recessive chromosome

Both parents known carriers of sex-linked recessive disorder

Patient or partner with balanced chromosomal translocation of his or her chromosomes

High or low AFP with accurate gestational age

Previous fetus with Down’s Syndrome

Prenatal Testing

Chorionic Villi Sampling- insertion of a needle through either the cervical os or through the abdomen, in conjunction with ultrasound, to obtain a sample of fetal tissue from the growing placenta for chromosomal analysis & other biochemical testsUsually done at 8-10 weeksIndications:

Patient prefers to make decision regarding pregnancy in the 1st trimester

Severe oligohydramnios

Prenatal Testing

Complications:Multiple gestationUterine bleeding during this pregnancyActive genital herpes or other cervical

infectionUterine fibroids

Takes 24-48 hours for initial results

Prenatal Testing

Percutaneous Umbilical Cord Sampling-removal of blood through a needle inserted through the abdomen and into the umbilical vein, in conjunction with ultrasoundPerformed from 18 weeks until termIndications:

Patient wants fast results to support decision regarding pregnancy

Abnormality is identified late in pregnancy

Prenatal Testing

More indications:Patient has been exposed to infectious

disease that could affect development of fetus

Blood incompatibility (Rh disease)Drug or chemical level is fetal blood

needs to be assessedFetal blood analysis 3 days

Postnatal Testing

Chromosome analysis/karyotype- photograph of the chromosomal make-up of an individual, including the number of chromosomes & any abnormalities

Polymerase Chain Reaction (PCR)- technique to copy small segments of DNA for analysis; useful in disorders with recurring mutations

High-resolution banding/prometaphase banding- useful for identification of subtle chromosomes

Postnatal Testing

Microarray- assesses the ability of mRNA molecules to and interact with DNA molecules; assesses gene expression within a single sample or in comparison to 2 different cell types or tissue samples; need only a small sample of blood or tissue; can be done on healthy or diseased tissue

Postnatal Testing

Fluorescence in situ hybridization (FISH)- cytogenic technique that can be used to detect and localize the presence or absence of specific DNA sequences on chromosomes; uses fluorescent probes that bind to only those parts of the chromosome with which they show a high degree of sequence similarity

Genetic Counseling

Goal- to assist the family in understandingDiagnosisRole of heredityRecurrence risks & optionsPossible courses of actionsMethods of ongoing adjustment

Genetic Counseling

IndicationsPreviously affected child, parent, or

grandparentCongenital malformationSensory defectMetabolic disorderMental retardationKnown or suspected chromosome

abnormalityNeuromuscular disorderDegenerative CNS disease

Genetic Counseling

More indicationsPreviously affected cousins

Muscular dystrophyHemophiliaHydrocephalus

ConsanguinityHazards of ionizing radiationRecurrent miscarriagesConcern for teratogenic effectAdvanced maternal ageHigh or low AFP

Newborn Care: Terminology

Birth defect- structural or functional abnormality of the body that is present from birth

Syndrome- group of anomalies that cannot otherwise be explained & occurs in similar patterns of expressions (ex. Fetal alcohol syndrome)

Sequence- primary anomaly that sets a pattern for other anomalies (Ex. Pierre Robin)

Newborn Care: Terminology

Association- nonrandom occurrence of multiple anomalies in 2 or more people (ex. CHARGE)

Malformation- abnormality of morphogenesis due to intrinsic problems within the developing structures (ex. Neural tube defect)

Deformation- abnormality of morphogenesis due to intrinsic problems within the developing structures (ex. uterine position defects)

Newborn Care: Terminology

Disruption- abnormality of morphogenesis due to disruptive forces or pressure acting on the developing structures (ex. Amniotic bands)

Genetic heterogeneity- different causes may produce different characteristics (ex. Hydrocephalus, cleft lip & palate)

Newborn Care

HistoryFamily

History of 3 generationsDefects in the family history related to

the problem with the childHistory of consanguinityReproductive history (frequent

miscarriages???)Pattern of inheritance of the problem

Newborn Care

PrenatalLength of gestationFetal activity levelMaternal exposure: infection, illness,

high fever, meds, alcohol, smoking, X-rays, known teratogens, illicit or prescription drug use

Obstetric factors: uterine malformations, labor complications, presenting fetal part

Neonatal factors: birth weight, length, HC, Apgar score

Newborn Care: Assessment

Physical ExamGeneral: asymmetry, inappropriate size &

lengthFace: configuration; centered features

with normal spacing; round, triangular, birdlike, elfin, or expressionless characteristics

Head: size of anterior fontanelle, prominence of frontal bone, flattened or prominent occiput, abnormalities in shape (large or small)

Newborn Care: Assessment

Skin: intact, presence of skin tags, open sinuses, tracts, etc.

Hair: texture, presence of whorlsEyes: structure, color of iris, presence of

colobomas, centering & spacing of epicanthal folds, ptosis, slanting, eyelash length

Ears: protruding or prominent shape, location, low set, unilateral or bilateral defect, presence &/or degree of rotation

Newborn Care: Assessment

Nose: beaked, bulbous, pinched, upturned, misshapen, two nares, flattened bridge, patency, centered on face

Oral: intact palate, presence of smooth philtrum, natal teeth, shape & size of tongue, mouth & jaw

Neck: short &/or webbed, redundant folds Chest: symmetric, presence of accessory

nipples, spacing of nipples, shape of chest

Newborn Care: Assessment

Abdomen: number of cord vessels, presence of bowel sounds; shape, presence or abd wall defects & abd wall musculature, prune belly

GU(male): hypospadius, chordee, ambiguous genitalia, descended testis

Anus: patency, presence, position

Newborn Care

Provide grief counseling Encourage genetic counseling Facilitate family use of available support

systems Provide emotional support

Newborn Care

Identify normal aspects of neonate that can coexist with neonate

Encourage parent participation in infant’s care

Discuss treatment options, including risks & benefits

Provide educational information Identify primary abnormality Recognize defects that may have more than

one cause

Newborn Care

Determine category of malformation, according to etiologyMalformationDeformationDisruptionSyndromeAssociationSequenceGenetic heterogeneity

VATER AssociationVertebral anomalies, Anal atresia, Tracheoesophageal fistula, Radial & renal dyspalsiaEtiology/precipitating factors: unknownClinical presentation

Vertebral anomaliesAnal atresia, with or without fistulaRadial dysplasia, including thumb or

radial hypoplasia, polydactyly, & syndactyly

Renal anomalySingle umbilical artery

VATER Association

ComplicationsFailure to thrivePossibility of normal life after slow

mental development during infancyCare

Supportive: prognosis & management depend on extent & severity of anomaly

Surgery: surgical correction of anomalies

VACTERL Association

Vertebral abnormalities, Anal atresia, Cardiac abnormalities, Tracheoesophageal fistula &/or esophageal atresia, Renal agenesis or dysplasia, & Limb defects

Etiology/precipitating factors: UnknownInjury between 4-6 weeks to a specific

mesodermal area may produce overstimulation of the hindgut, lower vertebral column, & developing kidney

Average of 7-8 abnormalities per patient

VACTERL Association

Clinical PresentationVertebral anomaliesAnal atresia with or without fistulaCardiac anomalies; commonly VSDsTEF with or without esophageal atresiaRadial Dysplasia, including thumb or

radial hypoplasia, polydactyly, & syndactyly

Renal anomalySingle umbilical artery

VACTERL Association

ComplicationsFailure to thriveNormal life: minimal CNS anomalies with

only occasional mental retardation Care:

Supportive: prognosis & management depend on extent & severity of anomaly

Surgery: surgical correction of anomalies

Trisomy 13

EtiologyMaternal age felt to be a factor47 chromosomes (3 of chromosome 13)20% of defects are caused by

translocations, some are familial5% occur as a result of mosaicism

Trisomy 13 Presentation

Growth deficiencyHead: microcephaly with sloping

forehead, midline scalp defectsEyes: abnormally close eyes,

microphthalmia, colobomas, glaucomaEars: low-set & malformed, atresia of

auditory canalsNose: prominent nasal bridgeMouth: bilateral cleft lip &/or palateNeck: short neck with excessive skin

Trisomy 13 Presentation Musculoskeletal

PolydactylyOverlapping of fingers with single palmar

creaseNarrow, hyperconvex fingernailsFlexion deformities of arms & wristsProminent heel resulting in rocker-bottom

feetGenitals: females (bicornate or septate

uterus); males (cryptorchidism, small scrotom)

Trisomy 13

Associated AnomaliesCardiac: VSDs, dextroposition, PDARenal abnormalities: cystic kidneysHoloprosencephalyCutaneous hemangiomasSeizure activitySevere deficits in cognitive & motor

development

Trisomy 13

ComplicationsLife expectancy: ~130 days, though 14%

survive to 1 year of ageCare is supportiveEducation & support for parents is

essential!

Trisomy 18

EtiologyAdvanced maternal ageMost affected fetuses are female (4:1)47 Chromosomes (3 of chromosome

18)90% occur due to nondisjunction

during meiosis

Trisomy 18Presentation

Growth deficiencyHead: microcephaly with prominent

occiputEyes: microphthalmia with narrow

palpebral fissures, colobomas, corneal opacities, hypoplasia of orbital ridges, ptosis of one or both eyes

Ears: low-set, poorly developed, often cup-shaped with large pinna, atresia of auditory canal

Trisomy 18

Mouth: micrognathia, microstomia, high-arched palate

Skin: excessive skin at nape of neck, widely-spaced nipples, decreased dermal creases due to decreased fetal movement

Trisomy 18

Musculoskeletal: clenched hand with index finger overlapping middle finger &/or 5th finger overlapping 4th finger, hypoplastic nails, rocker-bottom feet, prominent heels, hammertoes, syndactyly between 2nd & 3rd toes, short sternum with slender ribs, narrow pelvis with hip dysplasia

Trisomy 18 Associated findings

Cardiac abnormalities: various (VSD, PDA, pulmonary stenosis, coarctation of the aorta, etc.)

Renal anomalies: horseshoe kidneys, ectopic kidneys, double ureters, cystic kidneys

Genital abnormalities: cryptorchidism in males, hypoplasia of labia & prominent clitoris in females

Umbilical herniasSevere psychomotor retardation

Trisomy 18

Complications/Outcomes90% mortality rate within 1st year of lifeAnomalies are multiple & severeTreatment is supportiveParental Education, support, &

involvement are essential!

Trisomy 18

Trisomy 21

EtiologyRisk increases with maternal age though

~3/4 are born to mothers <3547 chromosomes ( 3 of chromosome 21)95% are complete trisomies; 2% are

mosaics; 3% are translocations Presentation

Head: small, round skull with flat occiput; flat facies due to lack of orbital ridges; flat nose; micrognathia

Trisomy 21

Eyes: upward slanting of palpebral fissures, Brushfield spots on iris, colobomatous cataracts, glaucoma, prominent epicanthal folds

Ears: low-set, boxy earsMouth: narrow, short palate; large

protruding tongueSkin: excess skin at nape of neck

Trisomy 21

PresentationMusculoskeletal: general hypotonia with

poor Moro reflex; hyperflexibility of joints; square hands with short fingers; transverse palmar crease; 5th fingers are short & curve inward due to absent or hypoplastic middle phalanx; low-set thumbs with greater than usual separation from index fingers

Trisomy 21

Presentation (Musculoskeletal): broad, short feet with wide space

between great toe & 2nd toe & deep creases that curve toward medial edge of foot; short stature; dysplasia of pelvis with narrow acetabular angle

Trisomy 21

Associated findingsPrematurityMental retardationCardiac abnormalities: endocardial

cushion defects (AV canal), VSD, PDAGI: duodenal atresia/stenosis, imperforate

anusHematologic: increased WBC count,

polycythemia, congenital leukemiaEndocrine: hypothyroidism

Trisomy 21

Complications/OutcomesAffected infants are mildly to severely

retarded (IQs range from 25-70)Parent education & support are essential

for continuing treatment of common health issuesFrequent URIs & ear infectionsCardiac sequelae, including CHFDevelopmental delays

Trisomy 21

References

Brodsky, D. & Martin, C. (2003). Neonatology Review. Hanley & Belfus, Inc.: Philadelphia.

Kenner, C. & Lott, L.W. (2007). Comprehensive Neonatal Care: An Interdisciplinary Approach (4th Edition). Saunders: St. Louis.

Siegfried, D.R. (2002). Anatomy & Physiology for Dummies. Wiley Publishing Inc: New York.

References

Thompson, G. (Ed). (2009). Anatomy & Physiology Made Incredibly Visual. Ambler, PA: Lippincott Williams & Wilkins.

Verklan, M.T. & Walden, M. (2004). Core Curriculum for Neonatal Intensive Care Nursing (3rd Edition). Elseiver Saunders: St. Louis.

References

www.ncbi.nlm.gov/About/primer/microarrays.html

www.ncbi.nlm.gov/books/bv.fcgi?rid-hmg.section.196

http://en.wikipedia.org/wiki/mosaic_(genetic)

http://en.wikipedia.org/wiki/chromatin