The Patterns of Genetic Inheritance By Dr. Joann Boughman, PhD Mendelian Non-Mendelian Autosomal Dominant Autosomal Recessive X-linked Recessive X-linked Dominant Y-linked Imprinting Mitochondrial Multifactorial Sporadic Contiguous gene syndromes

How to evaluate a pedigree... 1) Transmission: Are there affected family members in every generation (vertical pattern) or in only a single generation (horizontal pattern)? 2) Sex Differences: What is the ratio of affected males to females? 3) Segregation: Is disease/gene being passed through unaffected females? Is there male to male transmission? What % of children are affected (e.g. all of sons but none of daughters)?

…but don’t forget the complicating factors! Non-penetrance New mutation Adult-onset conditions Consanguinity Interaction Sex-limited/sex influenced Germline mosaicism Anticipation Heterogeniety Pleiotropy

Autosomal Dominant Vertical pattern: multiple generations affected Males and females equally likely to be affected See male to male transmission Each child of an affected individual has a 50% chance to be affected Unaffected individuals do pass on the gene Every affected child has an affected parent Adapted from The Pedigree: A Basic Guide, by Jorgenson, Yoder & Shapiro

Autosomal Dominant Non-Penetrance An individual who inherits the disease gene does not develop the disorder The disorder appears to “skip” generations Adapted from The Pedigree: A Basic Guide, by Jorgenson, Yoder & Shapiro

Autosomal Dominant Sex-Limited/Influenced 3 2 3 2 Gene expression limited to specific sex Disorder/trait may appear to “skip” generations Adapted from The Pedigree: A Basic Guide, by Jorgenson, Yoder & Shapiro

Autosomal Dominant New Mutation 3 3 2 An alteration occurs in the egg or sperm that made the affected individual (may be first family member to be affected) Recurrence risk for unaffected parents is considered to be low Risk of new mutation is associated with advanced paternal age in some disorders (e.g. Achondroplasia) Adapted from The Pedigree: A Basic Guide, by Jorgenson, Yoder & Shapiro

Autosomal Dominant Late-onset trait 4 3 4 3 2 dx 60 dx 50 dx 45 4 3 4 dx 45 3 2 An individual who inherits the disease gene but does not develop the condition until adulthood Examples: Huntington disease, most hereditary cancer syndromes Adapted from The Pedigree: A Basic Guide, by Jorgenson, Yoder & Shapiro

Autosomal Dominant Variable Expressivity Variability of severity of Lisch nodules café-au-lait spots Neurofibromas café-au-lait spots Lisch nodules café-au-lait spots scoliosis Variability of severity of disorder among individuals with same genotype Examples: Neurofibromatosis, Treacher-Collins syndrome Optic glioma learning disability neurofibromas café-au-lait spots

Autosomal Recessive Horizontal pattern: single generation affected. Males and females equally likely to be affected Parents of affected child are unaffected gene carriers and have a 1 in 4 or 25% recurrence risk Unaffected siblings have a 2/3 or 67% chance to be carriers. Children of affected individuals are obligate carriers. Adapted from The Pedigree: A Basic Guide, by Jorgenson, Yoder & Shapiro

Autosomal Recessive Consanguinity First cousins Autosomal Recessive Consanguinity Increased consanguinity (over general population) is often found between parents of a child with a rare autosomal recessive disorder Condition may appear to be dominant in a consanguineous family 2 2 Adapted from The Pedigree: A Basic Guide, by Jorgenson, Yoder & Shapiro

X-linked Recessive 2 3 4 2 3 2 Males are more often affected than females Affected males pass the gene to all of their daughters and none of their sons (NO male-to-male transmission) Daughters of carrier females have a 50% chance to be unaffected carriers. Sons of carrier females have 50% chance to be affected. Affected males in the family are related to each other through carrier females (“Knight’s move”)

X-linked Recessive Other characteristics 2 3 4 2 3 For genetically lethal X-linked conditions, 1/3 of isolated cases (i.e. no family history) are new mutations. In 2/3 of cases, the mother is an unaffected carrier Female gene carriers are usually not affected Exceptions: Turner syndrome, skewed X-inactivation, X;autosome translocation carriers

X-linked Dominant 2 2 For rare conditions, females are about 2x as likely to be affected than males. May be lethal in males and usually milder, but variable, in females. Affected males pass the gene to all of their daughters, who will be affected, and to none of their sons (NO male-to-male transmission) Sons and daughters of affected females have 50% chance of being affected (similar to autosomal dominant)

Y-linked (Holandric) 4 4 Only males are affected Affected males pass the disease gene to all their sons and to none of their daughters Adapted from The Pedigree: A Basic Guide, by Jorgenson, Yoder & Shapiro