germline mutation

**Definition:** A germline mutation occurs in the germ cells (or their precursors) and is incorporated into the gametes. If the mutated gamete participates in fertilization, the zygote and all of the child's somatic and germ cells carry the variant. Germline mutations can be transmitted to future generations. Somatic mutations arise after conception in non-gamete cells, are not heritable, and are limited to the affected cell clone.

**Key comparison (germline vs somatic):** - Germline: heritable, present in all cells, can cause congenital or familial disease, and is detectable in blood or any tissue. - Somatic: not heritable, mosaic or tumor-restricted, and the usual cause of sporadic cancers. Examples are BCR-ABL (the Philadelphia chromosome) in CML and JAK2 V617F in polycythemia vera.

**Inheritance and penetrance:** - Germline mutations follow Mendelian patterns: autosomal dominant (e.g., Huntington disease, Marfan syndrome, familial hypercholesterolemia), autosomal recessive (e.g., cystic fibrosis, sickle cell disease), or X-linked (e.g., Duchenne muscular dystrophy, hemophilia A). - Variable expressivity and incomplete penetrance are common (e.g., BRCA1, NF1). - De novo germline mutations arise in the gamete of an unaffected parent, so the child is affected with no family history. Advanced paternal age is associated with de novo point mutations (e.g., achondroplasia from FGFR3 mutation, Marfan syndrome, Apert syndrome).

**Germline mosaicism:** A mutation is present in a subset of a parent's gametes but not in their somatic cells. The parent is phenotypically normal, but there is a recurrence risk for siblings. Classic examples are osteogenesis imperfecta type II and Duchenne muscular dystrophy.

**Cancer genetics (high-yield):** - Knudson two-hit hypothesis: in hereditary cancer syndromes, the first hit (a tumor suppressor mutation) is germline, so every cell carries one defective allele. Only one additional somatic hit (loss of heterozygosity) is needed to lose function. Hereditary cancers therefore tend to have earlier onset, be bilateral or multifocal, and run in families. In sporadic cancers, both hits are somatic. - Syndromes: RB1 (retinoblastoma, osteosarcoma), TP53 (Li-Fraumeni), APC (FAP), MLH1/MSH2/MSH6/PMS2 (Lynch, mismatch repair), BRCA1/2 (breast, ovarian, prostate, pancreatic cancer), VHL, NF1/NF2, MEN1 (MEN1 gene) and RET (MEN2), and PTEN (Cowden). - Germline gain-of-function mutations in proto-oncogenes are rarer (e.g., RET in MEN2).

**Other mechanisms:** Germline mutation types include point mutations (missense, nonsense, silent), frameshifts, splice-site mutations, deletions or duplications, and trinucleotide repeat expansions. Repeat expansions show anticipation (e.g., Huntington disease, fragile X, myotonic dystrophy). Mitochondrial DNA mutations are germline but maternally inherited, with heteroplasmy and variable expression (e.g., MELAS, Leber hereditary optic neuropathy).

**Clinical significance:** - Germline testing uses blood or saliva (a multigene panel). It is indicated for early-onset cancers, multiple primaries, strong family history, or specific tumor features. - Results affect surveillance, risk-reducing surgery (e.g., prophylactic mastectomy or salpingo-oophorectomy in BRCA carriers, colectomy in FAP), targeted therapy (PARP inhibitors in BRCA-mutated tumors), and cascade testing of relatives. - Genetic counseling and the Genetic Information Nondiscrimination Act (GINA) protect patients from discrimination in health insurance and employment. - Tumor sequencing can incidentally reveal a germline variant, suggested by a variant allele fraction of about 50% or 100%.

**Pearls for boards:** "Present in every cell and heritable" is the hallmark of germline mutations. A new genetic disorder in a child with healthy parents suggests a de novo mutation (consider advanced paternal age) or germline mosaicism. Early-onset, bilateral, or familial cancer points to a germline mutation in a tumor suppressor gene.