GeneticsTier 1Medical Sciences concept

Somatic vs germline mutation - distinguishing features and propagation

Core concept

Germline mutation: present in the egg or sperm (or very early embryo) -- carried in every cell of the resulting individual, and heritable (can be passed to offspring)
Somatic mutation: arises in a single cell after fertilisation -- present only in that cell's descendants (a clonal population/tissue), not present in germ cells, not heritable
Distinguishing feature for testing: germline mutations are found in any tissue sampled (e.g. blood, skin); somatic mutations are found only in the affected tissue (e.g. tumour) and absent in a paired normal-tissue sample

CML (chronic myeloid leukaemia) BCR-ABL1 (Philadelphia chromosome, t(9;22)) is the classic somatic example -- arises in a single haematopoietic stem cell, found in leukaemic cells only, not present in skin/buccal cells, and not inherited by offspring
Contrast with a germline BRCA1 mutation -- present in blood, skin, every tissue tested, and transmissible to children with 50% (autosomal dominant) risk per pregnancy
Mosaicism sits between the two: a mutation arising early in embryonic development, present in some but not all tissues (including possibly germ cells) -- can cause somatic-tissue-limited disease, or gonadal mosaicism (mutation present in germ cells only) explaining unaffected parents having more than one affected child

Trap: testing blood for a suspected inherited cancer syndrome when the actual mutation is somatic and tumour-confined (e.g. sporadic CML) -- blood/germline testing will be normal, and a tumour sample is required to detect it
Cascade family testing is appropriate only for germline findings -- offering relatives testing for a mutation shown to be somatic (tumour-only) is inappropriate, since it cannot be inherited
Gonadal mosaicism explains apparent "de novo" cases recurring in a second sibling despite both parents testing negative on standard blood testing -- relevant to recurrence risk counselling after a single affected child

Directly relevant to Knudson two-hit hypothesis -- hereditary tumour syndromes have a germline first hit plus a somatic second hit in the tumour; sporadic cancers have two somatic hits
Tumour genomic profiling (paired tumour/normal sequencing) is specifically designed to separate somatic (tumour-only) from germline (found in both) variants
Mosaicism concepts also apply outside cancer (e.g. segmental neurofibromatosis, some skeletal dysplasias) -- same "not every cell affected" principle in a non-malignant context

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