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BSC SEM 4 UNIT 3 PATHOLOGY 2 & GENETICS.

UNIT 3 Genetic testing in the neonates and children

INTRODUCTION.

Genetic testing in neonates and children involves analyzing DNA to detect genetic abnormalities, disorders, or susceptibilities at an early age. This testing can significantly influence medical decisions, treatment options, and preventive care measures.

Types of Genetic Testing in Neonates and Children:

  1. Newborn Screening
    • Performed routinely shortly after birth.
    • Screens for metabolic, endocrine, hematological, and genetic disorders (e.g., phenylketonuria, congenital hypothyroidism, cystic fibrosis, sickle cell anemia).
  2. Diagnostic Genetic Testing
    • Conducted when a child exhibits symptoms suggestive of a genetic disorder.
    • Helps confirm specific conditions (e.g., Down syndrome, fragile X syndrome, Duchenne muscular dystrophy).
  3. Carrier Testing
    • Identifies carriers who do not exhibit symptoms but may pass genetic conditions to their offspring (more common in older children and adolescents).
  4. Predictive and Presymptomatic Testing
    • Identifies genetic conditions before symptoms appear, especially useful if a family history exists (e.g., Huntington’s disease, hereditary cancers).
  5. Chromosomal Microarray Analysis (CMA)
    • Detects submicroscopic genetic abnormalities responsible for developmental delays, autism spectrum disorders, or congenital anomalies.
  6. Whole Exome Sequencing (WES) & Whole Genome Sequencing (WGS)
    • Comprehensive genetic testing methods identifying rare and previously unidentified genetic mutations.

Indications for Genetic Testing in Neonates and Children:

  • Developmental delays or intellectual disabilities.
  • Multiple congenital anomalies.
  • Suspected inherited metabolic disorders.
  • Positive family history of genetic conditions.
  • Failure to thrive or unexplained growth abnormalities.
  • Neurological symptoms or seizures without clear etiology.

Benefits of Genetic Testing:

  • Early diagnosis and timely intervention.
  • Targeted treatment and personalized medical management.
  • Genetic counseling to inform family planning.
  • Reduction in morbidity and mortality through proactive care.

Ethical and Psychosocial Considerations:

  • Consent and autonomy: Parental consent is crucial; as the child grows, personal autonomy in decisions about genetic information becomes important.
  • Psychological impact: Early genetic diagnosis can cause emotional distress, anxiety, or stigmatization.
  • Privacy and confidentiality: Protecting genetic information from misuse or discrimination (e.g., insurance or employment issues).

Procedure:

  1. Sample Collection:
    • Blood (most common), saliva, buccal swab, skin biopsy, or amniotic fluid (prenatal testing).
  2. Laboratory Analysis:
    • DNA extraction and genetic sequencing or analysis.
  3. Result Interpretation:
    • Conducted by clinical geneticists or genetic counselors, who translate findings into practical guidance for families.
  4. Follow-Up:
    • Genetic counseling, medical management, family education, and psychosocial support.

Common Genetic Disorders Identified Through Neonatal Genetic Testing:

  • Cystic fibrosis
  • Phenylketonuria (PKU)
  • Sickle cell anemia
  • Congenital hypothyroidism
  • Galactosemia
  • Fragile X syndrome
  • Spinal muscular atrophy (SMA)

Recommendations for Health Professionals:

  • Obtain informed consent clearly explaining the benefits, limitations, and potential implications of genetic tests.
  • Provide counseling and support before, during, and after genetic testing.
  • Refer families to appropriate genetic services, multidisciplinary clinics, and support groups.

1. Newborn Screening (NBS)

  • Performed shortly after birth (usually within 48–72 hours).
  • Uses dried blood samples collected on special filter paper (Guthrie cards).

Techniques Used:

  • Tandem Mass Spectrometry (MS/MS):
    • Detects multiple metabolic disorders simultaneously, such as Phenylketonuria (PKU), Maple syrup urine disease (MSUD), and organic acid disorders.
  • Enzyme Assays:
    • Identifies conditions like Galactosemia and Biotinidase deficiency by measuring enzyme activity.
  • Immunoassays (e.g., ELISA):
    • Used to screen for congenital hypothyroidism, cystic fibrosis, and congenital adrenal hyperplasia by detecting specific hormones or proteins.

Examples of Conditions Screened:

  • Phenylketonuria (PKU)
  • Congenital Hypothyroidism
  • Galactosemia
  • Sickle Cell Disease
  • Cystic Fibrosis

2. Chromosomal Microarray Analysis (CMA)

  • Detects submicroscopic chromosomal abnormalities causing developmental delays, intellectual disabilities, autism, and congenital anomalies.
  • More precise than traditional karyotyping, identifying smaller deletions and duplications.

Conditions detected:

  • Microdeletion syndromes (e.g., DiGeorge syndrome, Cri-du-chat syndrome)
  • Copy-number variations associated with autism spectrum disorders and intellectual disabilities

3. Cytogenetic Testing (Karyotyping)

  • Evaluates the number and structure of chromosomes in blood or tissue samples.
  • Typically used when chromosomal disorders are suspected clinically.

Conditions detected:

  • Down syndrome (Trisomy 21)
  • Turner syndrome (45, XO)
  • Klinefelter syndrome (47, XXY)

4. Molecular Genetic Testing (DNA-based)

  • Polymerase Chain Reaction (PCR) and Sequencing:
    • Used for detecting single-gene (monogenic) disorders and gene mutations.
  • Whole Exome Sequencing (WES):
    • Analyzes the protein-coding genes; effective in diagnosing rare or unknown genetic diseases.
  • Whole Genome Sequencing (WGS):
    • Comprehensive testing of entire genome, used when other tests fail to identify a genetic defect.

Conditions detected:

  • Cystic fibrosis
  • Fragile X syndrome
  • Duchenne muscular dystrophy
  • Spinal Muscular Atrophy (SMA)

5. Imaging and Ultrasound Screening

  • Imaging techniques such as ultrasonography, MRI, or X-rays used to detect anatomical malformations associated with genetic syndromes.

Conditions detected:

  • Congenital heart defects (commonly associated with Down syndrome)
  • Neural tube defects (e.g., spina bifida)

6. Biochemical Screening

  • Measurement of abnormal levels of metabolites, enzymes, or hormones in blood, urine, or cerebrospinal fluid.
  • Particularly used for metabolic disorders.

Conditions detected:

  • Tay-Sachs disease (enzyme deficiency testing)
  • Galactosemia (galactose metabolite)
  • Organic acidurias (organic acids in urine)

7. Carrier Screening

  • Performed in older children or adolescents, especially those with a family history, to assess carrier status.
  • Useful for identifying asymptomatic carriers who may transmit disorders to future generations.

Flowchart for Neonatal Genetic Screening:

  1. Birth: Blood spot collection → Initial screening.
  2. Positive Screening Result: Confirmatory testing (DNA analysis, enzyme assays, imaging).
  3. Diagnosis Confirmed: Early treatment, genetic counseling, and family support initiated.
  4. Negative Result: Regular pediatric follow-up and developmental surveillance.

Ethical Considerations:

  • Obtaining informed parental consent.
  • Counseling about possible outcomes, false positives, and false negatives.
  • Ensuring confidentiality and appropriate handling of genetic information.

Importance:

  • Early identification reduces disease severity.
  • Enables timely medical and nutritional interventions.
  • Facilitates informed decisions about future pregnancies.

Screening for Congenital Abnormalities

Congenital abnormalities, also known as birth defects, are structural or functional anomalies present at birth. Early screening identifies these defects, enabling timely intervention, management, and improved health outcomes.

Purpose of Screening

  • Early detection of anatomical, structural, or functional defects.
  • Timely medical, surgical, or therapeutic intervention.
  • Providing informed counseling to families.

Common Congenital Abnormalities Screened

  • Congenital heart defects (CHDs)
  • Neural tube defects (spina bifida, anencephaly)
  • Cleft lip/palate
  • Chromosomal abnormalities (Down syndrome, Edwards syndrome, Turner syndrome)
  • Limb defects (clubfoot)
  • Gastrointestinal abnormalities (esophageal atresia, anorectal malformations)
  • Renal anomalies (polycystic kidneys, hydronephrosis)
  • Congenital hearing loss
  • Congenital cataracts or vision impairment

Methods of Screening for Congenital Abnormalities

1. Prenatal Screening (During Pregnancy)

a. Ultrasound (Sonography)

  • First Trimester (11-13 weeks):
    • Nuchal translucency measurement (screening for Down syndrome and chromosomal defects).
  • Second Trimester (18-22 weeks; Anomaly Scan):
    • Detailed anatomical scan for structural defects like congenital heart disease, cleft lip/palate, neural tube defects, limb abnormalities, and other anomalies.

b. Maternal Serum Screening (Biochemical Tests)

  • Double Marker Test (First Trimester):
    • Beta-hCG, Pregnancy-associated plasma protein-A (PAPP-A).
    • Risk assessment for chromosomal disorders (Down syndrome, Trisomy 13/18).
  • Triple or Quadruple Marker Test (Second Trimester):
    • Alpha-Fetoprotein (AFP), Beta-hCG, Estriol, Inhibin-A.
    • Detection of neural tube defects, Down syndrome, Edwards syndrome.

c. Non-Invasive Prenatal Testing (NIPT)

  • Blood test analyzing fetal DNA circulating in maternal blood.
  • Screens for chromosomal abnormalities (Trisomy 21, 18, 13) with high accuracy.

d. Invasive Prenatal Diagnosis (Confirmatory)

  • Amniocentesis (15-20 weeks): Analysis of fetal cells from amniotic fluid.
  • Chorionic Villus Sampling (CVS) (10-13 weeks): Analysis of placental cells.
  • Indicated for high-risk pregnancies or abnormal screening results.

2. Neonatal Screening (After Birth)

a. Physical Examination at Birth

  • Detailed physical exam (head-to-toe assessment) by pediatrician/neonatologist to detect structural abnormalities:
    • Cleft palate/lip
    • Congenital hip dislocation
    • Neural tube defects
    • Limb deformities
    • External genitalia anomalies

b. Pulse Oximetry Screening

  • Detection of critical congenital heart defects (CCHDs).
  • Measurement of oxygen saturation (>95% is normal).
  • Done at 24–48 hours of life.

c. Hearing Screening

  • Universal newborn hearing screening program (within first month).
  • Techniques:
    • Otoacoustic Emissions (OAE)
    • Automated Auditory Brainstem Response (AABR)

d. Newborn Blood Spot Test (Metabolic Screening)

  • Screens metabolic, genetic, endocrine, and hematological disorders, some of which accompany congenital abnormalities (e.g., congenital hypothyroidism, congenital adrenal hyperplasia).

3. Imaging Techniques in Infants and Children

  • Ultrasound
    • Detect renal anomalies (hydronephrosis, polycystic kidneys).
    • Hip ultrasound for congenital dysplasia/dislocation.
  • Echocardiography
    • Detailed imaging of congenital heart defects.
  • MRI/CT Scan
    • In-depth structural analysis (e.g., neural defects, brain abnormalities, skeletal malformations).
  • X-rays
    • Skeletal anomalies (e.g., limb deformities, congenital diaphragmatic hernia).

Follow-up and Management

  • Confirmatory testing, genetic counseling.
  • Multidisciplinary team management (pediatrician, neonatologist, geneticist, cardiologist, neurologist, surgeons, therapists).
  • Supportive interventions (surgical repair, rehabilitation, prosthetics, hearing aids).

Ethical Considerations

  • Informed parental consent and counseling.
  • Psychological support to parents/family.
  • Confidentiality and proper use of genetic information.

Importance of Screening

  • Early detection and intervention lead to better outcomes.
  • Reduces infant morbidity and mortality.
  • Prepares families emotionally, socially, and financially for special care needs.

Understanding Developmental Delay

Developmental delay refers to a significant lag in achieving age-appropriate developmental milestones in motor, cognitive, language, social, or emotional skills. Genetic disorders are among common causes of developmental delays, making early screening and detection crucial.

Why Screening is Essential:

  • Early Identification: Helps in prompt intervention.
  • Effective Management: Allows personalized care strategies.
  • Improved Outcomes: Reduces severity, improves quality of life.

Common Genetic Conditions Linked to Developmental Delay:

  • Down Syndrome (Trisomy 21)
  • Fragile X Syndrome
  • Rett Syndrome
  • Angelman Syndrome
  • Prader-Willi Syndrome
  • Metabolic disorders (e.g., Phenylketonuria)
  • Autism spectrum disorders (with genetic factors)

Screening Methods for Genetic Defects and Diseases:

1. Developmental Surveillance and Screening

  • Regular pediatric check-ups.
  • Monitoring developmental milestones:
    • Gross motor: Walking, crawling.
    • Fine motor: Grasping objects.
    • Language: Speech and comprehension.
    • Social/Emotional: Interaction, eye contact, play skills.

Tools used:

  • Ages and Stages Questionnaires (ASQ)
  • Denver Developmental Screening Test (DDST-II)

2. Newborn Metabolic and Genetic Screening

Performed within 48–72 hours after birth via blood sample (heel-prick test).

Techniques used:

  • Tandem Mass Spectrometry (MS/MS): Detects metabolic disorders (e.g., Phenylketonuria, hypothyroidism).
  • Enzyme Assays: Identifies enzyme deficiency diseases (e.g., Galactosemia, Biotinidase deficiency).
  • Immunoassays: Detect conditions like Congenital hypothyroidism, Cystic fibrosis.

3. Cytogenetic Testing

Karyotype Analysis:

  • Detects abnormal chromosome numbers or structures.
  • Used in suspected Down syndrome, Turner syndrome, Klinefelter syndrome.

4. Chromosomal Microarray Analysis (CMA)

  • Identifies small deletions or duplications (copy-number variations).
  • Highly effective in evaluating unexplained developmental delay, intellectual disability, autism.

Conditions Detected:

  • DiGeorge syndrome (22q11.2 deletion)
  • Williams syndrome (7q11 deletion)
  • Prader-Willi/Angelman syndrome (15q11-q13 abnormalities)

5. Molecular Genetic Testing (DNA-based)

  • Polymerase Chain Reaction (PCR) & DNA Sequencing: For identifying specific genetic mutations causing delays.
  • Whole Exome Sequencing (WES): Analyzes protein-coding genes; beneficial when traditional tests fail.
  • Whole Genome Sequencing (WGS): Detailed analysis of entire genome, valuable in undiagnosed developmental delays.

Conditions Detected:

  • Fragile X Syndrome (FMR1 gene mutation)
  • Rett syndrome (MECP2 gene mutation)

6. Neuroimaging Techniques

  • MRI/CT Scan: Identifies structural brain abnormalities causing delays.
  • Helps detect disorders such as brain malformations, cerebral palsy, or hydrocephalus.

7. Hearing and Vision Screening

  • Conducted soon after birth and during regular checkups.
  • Important as sensory impairments significantly contribute to developmental delays.

Techniques:

  • Hearing: Otoacoustic Emissions (OAE), Automated Auditory Brainstem Response (AABR).
  • Vision: Retinoscopy, visual acuity screening.

Step-by-step Approach to Genetic Screening in Developmental Delay

  1. Initial Clinical Evaluation:
    • Thorough history and physical examination.
    • Assessment of developmental milestones.
  2. First-tier Investigations:
    • Hearing and vision tests.
    • Metabolic and newborn screening review.
  3. Second-tier Investigations:
    • Chromosomal Microarray (CMA).
    • Cytogenetic testing (Karyotyping).
  4. Third-tier Investigations (Advanced Genetics):
    • Molecular genetic testing (WES or WGS).
    • Neuroimaging (MRI).
  5. Follow-up and Multidisciplinary Intervention:
    • Genetic counseling for families.
    • Medical management, special education, physical therapy, speech therapy.

Ethical Considerations:

  • Informed consent from parents.
  • Privacy and confidentiality of genetic data.
  • Psychological counseling and support.

Importance of Genetic Screening:

  • Early intervention significantly improves developmental outcomes.
  • Facilitates targeted therapies.
  • Guides family planning and genetic counseling.

Understanding Dysmorphism

Dysmorphism refers to distinct physical features or structural anomalies that deviate from typical anatomical appearance, often indicating an underlying genetic syndrome or chromosomal abnormality. Early detection through screening is critical for timely diagnosis, intervention, and counseling.

Purpose of Screening for Dysmorphism:

  • Early identification of genetic or syndromic disorders.
  • Facilitating prompt medical, surgical, or therapeutic interventions.
  • Providing genetic counseling to affected families.

Common Genetic Conditions Associated with Dysmorphism:

  • Chromosomal Disorders:
    • Down Syndrome (Trisomy 21)
    • Edwards Syndrome (Trisomy 18)
    • Patau Syndrome (Trisomy 13)
  • Microdeletion/Microduplication Syndromes:
    • DiGeorge Syndrome (22q11 deletion)
    • Williams Syndrome (7q11 deletion)
    • Cri-du-chat Syndrome (5p deletion)
  • Single-gene Syndromes:
    • Noonan Syndrome
    • Marfan Syndrome
    • Achondroplasia
    • Cornelia de Lange Syndrome
    • Treacher Collins Syndrome

Screening Methods for Dysmorphism

1. Clinical Examination

Physical and Dysmorphology Examination:

  • Comprehensive physical examination at birth and follow-ups.
  • Observation of head, face, ears, eyes, hands, feet, genitalia, and skin for characteristic anomalies.

Features Assessed:

  • Facial abnormalities (low-set ears, flat nasal bridge, widely spaced eyes)
  • Limb anomalies (short limbs, extra fingers/toes)
  • Cranial shape abnormalities (microcephaly or macrocephaly)
  • Palatal defects (cleft lip/palate)
  • Skin anomalies (birthmarks, café-au-lait spots)

2. Prenatal Screening (Ultrasound and Maternal Serum)

a. Ultrasound Screening

  • First Trimester (11–13 weeks): Nuchal translucency for chromosomal defects.
  • Second Trimester (18–22 weeks): Detailed anomaly scan assessing for structural malformations indicating syndromic dysmorphism (e.g., cleft lip/palate, limb defects).

b. Maternal Serum Markers

  • Triple or Quadruple tests for chromosomal abnormalities:
    • AFP (Alpha-fetoprotein)
    • hCG (human Chorionic Gonadotropin)
    • Estriol, Inhibin-A

c. Non-invasive Prenatal Testing (NIPT)

  • Detects fetal chromosomal abnormalities (Trisomy 21, 18, 13) from maternal blood with high sensitivity.

3. Cytogenetic Testing (Karyotyping)

  • Evaluates chromosome number and structure from peripheral blood or tissues.
  • Essential in evaluating conditions like:
    • Down Syndrome (47,XX/XY +21)
    • Turner Syndrome (45,XO)
    • Edwards Syndrome (47,XX/XY +18)

4. Chromosomal Microarray Analysis (CMA)

  • Detects subtle chromosome abnormalities (microdeletions and duplications).
  • Essential for evaluating dysmorphic features with intellectual disability or developmental delay.

Conditions Detected:

  • DiGeorge Syndrome (22q11 deletion)
  • Williams Syndrome (7q11 deletion)
  • Cri-du-chat Syndrome (5p deletion)

5. Molecular Genetic Testing (DNA Testing)

  • Targeted Gene Sequencing (PCR & DNA sequencing):
    • Diagnoses specific genetic syndromes based on clinical suspicion.
    • Conditions: Noonan syndrome, Marfan syndrome, Achondroplasia, Apert syndrome.
  • Whole Exome Sequencing (WES):
    • Analyzes coding regions of genes.
    • Useful when specific syndrome is uncertain.
  • Whole Genome Sequencing (WGS):
    • Comprehensive genetic analysis when standard testing fails.

6. Imaging Techniques

a. Ultrasound/MRI

  • Identifies internal organ anomalies associated with dysmorphic syndromes:
    • Congenital heart defects (common in Down syndrome, DiGeorge syndrome)
    • Renal anomalies
    • Brain malformations (microcephaly)

b. X-ray/Skeletal Survey

  • Identifies skeletal anomalies characteristic of certain syndromes (e.g., achondroplasia, osteogenesis imperfecta).

Step-by-Step Screening Approach for Dysmorphism

  1. Clinical Evaluation:
    • Dysmorphology assessment by neonatologist or pediatrician.
  2. Prenatal Screening Review:
    • Review prenatal ultrasound and biochemical screening.
  3. First-tier Genetic Testing:
    • Cytogenetic testing (Karyotype analysis).
    • Chromosomal Microarray (CMA).
  4. Second-tier Genetic Testing:
    • Molecular DNA testing (Targeted gene sequencing, WES/WGS).
  5. Imaging Investigations:
    • Ultrasound, Echocardiography, MRI, X-ray for associated anomalies.
  6. Multidisciplinary Management:
    • Genetic counseling, family support, specialized medical or surgical interventions.

Ethical Considerations:

  • Informed parental consent.
  • Psychological counseling for families coping with a diagnosis.
  • Maintaining confidentiality and privacy of genetic data.

Importance of Screening:

  • Early diagnosis improves clinical outcomes.
  • Allows timely management and intervention.
  • Provides accurate information for genetic counseling and future family planning.
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