Pedigree charts

Definition and Concepts

A pedigree chart constitutes a standardized graphical representation of a family's medical history and genetic relationships across multiple generations.
It maps the biological relationships and the segregation of specific clinical traits, genetic diseases, or phenotypes within a kindred.
Drawing and interpreting a pedigree acts as an inexpensive and integral tool for diagnosing single gene disorders.
Proband (Index Case): The affected individual through whom a family comes to medical attention, indicated by an arrow.
Consultand: The individual seeking genetic counselling or testing.
Kindred: The extended family depicted in the chart.

Pedigrees utilize standardized symbols recommended by the National Society of Genetic Counselors (NSGC) to ensure universal interpretability.

Symbol / Feature	Interpretation
Square	Male.
Circle	Female.
Diamond	Gender unspecified.
Triangle	Pregnancy loss or spontaneous abortion.
Unshaded Symbol	Unaffected individual.
Fully Shaded Symbol	Clinically affected individual.
Half-Shaded Symbol	Carrier of an autosomal recessive trait.
Central Dot	Carrier of an X-linked recessive trait.
Diagonal Line Through Symbol	Deceased individual.
Single Horizontal Line	Mating or partnership.
Double Horizontal Line	Consanguineous mating.
Horizontal Line Above Siblings	Sibship line, with offspring drawn left to right in birth order.
Inverted V connected by horizontal line	Monozygotic twins.
Inverted V without connecting line	Dizygotic twins.
Symbol with internal 'P'	Ongoing pregnancy.
Brackets around symbol	Adopted individual.

Generation Depth: Documentation requires a minimum of three generations, encompassing the proband, parents, aunts, uncles, and grandparents.
Information Gathering: Involves systematic inquiry regarding health status, age at diagnosis, and cause of death for each relative.
Targeted Questioning: Requires specific inquiries regarding consanguinity, recurrent miscarriages, stillbirths, neonatal deaths, and developmental delays to identify underlying genetic etiologies.
Documentation Standards: Must include the date of construction, historian name, and clinician signature to ensure clinical validity.

Characterized by vertical transmission seen in every generation.
Approximately 50% of offspring of an affected parent inherit the condition.
Males and females are affected with equal frequency and severity.
Presence of male-to-male transmission confirms AD and distinguishes it from X-linked inheritance.

Demonstrates horizontal transmission, often limited to a single sibship within one generation.
Parents of an affected child are typically asymptomatic obligate carriers.
Recurrence risk equals 25% for subsequent pregnancies.
Increased prevalence observed in consanguineous families.

X-Linked Recessive (XLR): Exhibits diagonal transmission. Predominantly affects males. No male-to-male transmission occurs. Carrier females have a 50% chance of transmitting the mutation to sons.
X-Linked Dominant (XLD): Affects both sexes but is often lethal in males. Affected males transmit the trait to 100% of daughters and 0% of sons.
Y-Linked (Holandric): Strict male-to-male transmission.
Mitochondrial (Maternal): Matrilineal transmission where an affected mother transmits the mutation to all offspring. Affected males do not transmit the trait.

Incomplete Penetrance: An individual possesses the pathogenic genotype but lacks the disease phenotype, resulting in skipped generations in an AD pedigree.
Variable Expressivity: Individuals with identical genetic mutations exhibit varying degrees of clinical severity.
De Novo Mutations: A novel genetic alteration appearing for the first time in a family, often mimicking recessive inheritance initially but posing a dominant risk to the proband's future offspring.
Germline Mosaicism: Suspected when phenotypically normal parents have multiple children with a highly penetrant AD or X-linked disorder.

Diagnosis: Facilitates pattern recognition, narrows differential diagnosis, and guides the selection of molecular genetic tests.
Risk Assessment: Provides the foundation for calculating recurrence risks for parents and asymptomatic relatives.
Variant Interpretation: Crucial for resolving the pathogenicity of Variants of Uncertain Significance (VUS) identified on exome or genome sequencing through co-segregation analysis.

Recall Bias: Dependence on incomplete or inaccurate family memory regarding historical diagnoses or infant deaths.
Non-Paternity: Misattributed parentage can completely invalidate recurrence risk calculations.
Incidental Findings: May inadvertently reveal sensitive secrets, including undisclosed adoptions or incest.