Table 1.
Candidate examples of combined somatic and germ line mosaicism in genetic disorders.
| Disorder and Clinical Status of Affected Offspring | Gene and Chromosome | Somatic Mosaicism in Parent * | Germ Line Mosaicism in Parent * | Mosaic Parent and Clinical Status |
|---|---|---|---|---|
| X-linked dominant protoporphyria [55], One severely affected | ALAS2 ChrX | Yes Sequencing, 13% mutant allele in peripheral blood and buccal mucosa | Yes Aff/unaff half-sibs share same maternal X haplotype with/without mutation | Mother Mildly affected |
| Androgen insensitivity [56] Two siblings differentially affected, one raised as female one as male | AR ChrX | Yes Allele specific oligo hybridization <10% mutant allele in peripheral blood | Yes Aff/unaff sibs share same maternal X haplotype with/without mutation | Mother Unaffected |
| Osteogenesis imperfecta [57] Two half-siblings, one deceased pre-term, one deceased neonatally | COL1A1 Chr17 | Yes RFLP, 20% mutant allele in peripheral blood, hair bulbs, absence of mutant allele in fibroblasts | Yes RFLP, 14% mutant allele in sperm | Father Unaffected |
| Osteogenesis imperfecta [58] One deceased perinatally | COL1A1 Chr17 | Probably Allele-specific hybridization, variable proportion mutant allele 26% in peripheral blood 45%–50% in fibroblasts | Probably Allele-specific hybridization, 36%–40% mutant allele in sperm | Father Mildly affected |
| Osteogenesis imperfecta [59] Two siblings, one more severe deceased at 3 years | COL1A1 Chr17 | Yes Allele specific hybridization, library colony count, variable proportion mutant allele in peripheral blood (~10%), fibroblasts (~25%) | Possibly Allele specific hybridization, library colony count, 40%–45% mutant allele in sperm | Father Unaffected |
| Osteogenesis imperfecta [60] Two half-siblings, severely affected deceased neonatally | COL1A2 Chr7 | Probably Southern blot, variable stoichiometry of mutant allele in peripheral blood (40%), fibroblasts (almost 50%) | Probably Southern blot, 40% mutant allele in sperm | Father Moderately affected |
| Osteogenesis imperfecta [61] One affected proband, two deceased prenatally | COL1A2 Chr7 | Yes 25% mutant allele in peripheral blood, fibroblasts | Possibly 40% mutant allele in sperm | Father Unaffected |
| Rubinstein-Taybi syndrome [62] One significantly affected (FII) | CREBBP Chr16 | Possibly Sanger sequencing, small secondary peak of mutant allele in saliva, blood (not quantified) | Possibly Sanger sequencing, small secondary peak of mutant allele in sperm (not quantified) | Father Very mildly affected if at all |
| Dyskeratosis congenital [63] Two affected males, two unaffected mutation carrier het females with skewed X-inactivation | DKC1 ChrX | Yes Allele-specific PCR, mutant allele observed but <5% in peripheral blood, saliva | Yes Aff/unaff brothers share same maternal X haplotype with/without mutation | Mother Unaffected |
| Duchenne muscular dystrophy [64] Family DL114, one affected proband | DMD ChrX | Possibly Southern blot, mutant allele band less than 50% in peripheral blood | Yes Aff/unaff sibs share same maternal X haplotype with/without mutation | Mother |
| Duchenne muscular dystrophy [65] Proband hemizygous, severely affected from age 3 years | DMD ChrX | Yes Microsatellite genotyping and PCR deletion detection Three alleles detected in maternal lymphocytes | Yes Aff/unaff brothers share same maternal X haplotype with/without mutation | Mother Unaffected |
| Haemophilia B [66] One severely affected hemizygous male of heterozygous mother, mosaicism analyzed in her father (“grandfather”) | FIX ChrX | Yes DHPLC, 35% mutant allele in peripheral blood | Yes Aff/unaff half-sisters share same grandpaternal X haplotype with/without mutation | Grandfather Mildly affected in clotting assay |
| Facioscapulohumeral muscular dystrophy [67] One affected in each of two families (F4, F13) | FSHD1 Chr4 | Probably Southern blot Signal of mutant versus normal RFLP band in peripheral blood lower than in non-mosaic affected progeny (semi-quantitative) | Yes Southern blot Aff/unaff sibs share same maternal haplotype with/without mutation in both families | Mothers (2 families) Possibly affected |
| Haemophilia A [68] One affected male proband, mutation from mosaic mother | FVIII ChrX | Possibly Southern blot, causal mutant allele much less than 50% in peripheral blood | Possibly Southern blot, three gene alleles among progeny | Mother Unaffected |
| Haemophilia A [69] One affected male proband, mutation from heterozygous unaffected mother, mosaic was maternal grandfather | FVIII ChrX | Yes Sequencing and PAGE, normal and mutant allele of X-linked gene present in peripheral blood, buccal cells | Yes Sequencing and PAGE, 2 sisters of proband’s mother, normally obligate mutation carriers, lacked mutant allele | Grandfather Unaffected |
| Lesch-Nyhan syndrome [70] Proband hemizygous for mutation, undiagnosed brother deceased age 1 month | HPRT1 ChrX | Yes Cultured cell clones with or without mutation | Yes Aff/unaff sisters share same maternal X haplotype with/without mutation (heterozygous) | Mother Unaffected |
| Hunter disease [71] Proband hemizygous for mutation | IDS ChrX | Yes Allele-specific hybridization, quantitative PCR, variable mutant allele frequencies 7% in lymphocytes, leukocytes, 22% in fibroblasts, 1/35 hair bulbs | Yes Aff/unaff brother/sister share same maternal X haplotype with/without mutation | Mother Unaffected |
| CRASH syndrome [72] Proband hemizygous for mutation, mother heterozygous carrier, one affected hemizygous uncle | L1CAM ChrX | Yes RFLP, SSCP, mutant allele signal less than in true heterozygotes in family. | Yes Aff/unaff siblings share same grandmaternal X haplotype with/without mutation | Grandmother Unaffected |
| Neurofibromatosis [73] Mosaic mother is proband, affected daughter simple heterozygote for mutation | NF2 Chr22 | Yes Quantitative Sanger sequencing, 18% mutant allele in peripheral blood | Yes Aff sister/unaff brother share same maternal haplotype with/without mutation | Mother Affected diagnosed age 23 years |
| Lowe syndrome [74] One affected hemizygous mutation carrier in family LS04FR, heterozygous unaffected mother | OCRL ChrX | Possibly Single strand conformation analysis, small proportion of mutant allele detected in urine, none in blood, buccal or hair bulb | Yes 1 carrier, 2 normal sisters share same grandmaternal X haplotype with/without mutation | Grandmother Unaffected |
| Hypophosphatemic rickets [75] One affected diagnosed age 19 months, 56% mutant allele as per simple heterozygote | PHEX ChrX | Yes Single-base extension and DHPLC, 60% mutant allele in lymphocytes, 6%–94% mutant allele in multiple independent hair bulbs | Yes Aff/unaff sisters share same paternal X haplotype with/without mutation (heterozygous) | Father Affected, treatment initiated age 2 years, grandparents unaffected |
| Polycystic kidney disease [76] One affected diagnosed age 17 years | PKD1 Chr16 | Yes Next-generation sequencing, 3% mutant allele in peripheral blood, 4% in buccal cells (below detection limit by Sanger sequencing) | Yes Sanger, next-generation sequencing, 10% mutant allele in sperm | Father Affected, diagnosed age 50 years |
| Alzheimer disease [77] Mosaic mother is proband, onset age 42 years, deceased age 58 years. One daughter inherited mutation fully heterozygous, more severe, onset age 27 years, deceased age 39 years | PSEN1 Chr14 | Yes Allele-specific hybridization, mutant allele in peripheral blood, autopsy cerebral cortex much lower signal than in heterozygous daughter (qualitative), mutant detected by sequencing cerebral cortex but not peripheral blood DNA | Yes 1 aff/2 unaff sibs share same maternal haplotype with/without mutation | Mother Affected |
| Retinoblastoma [78] Three families (139, 345, 385) each with one bilaterally affected proband | RB1 Chr13 | Yes PCR SSCP, mutant allele less than 50% in peripheral blood in all three mosaic parents | Yes Aff/unaff sibs share same parental haplotype with/without mutation (all 3 families). In one family, mutation observed in 20%–30% of father’s sperm | Father (two families) Mother (one family) All unaffec ted |
| Retinoblastoma [79] Families D, E one bilaterally affected proband in each | RB1 Chr13 | Yes RFLP, sequencing individual PCR clones from peripheral blood, 10% clones mutation positive in fam D, 12% in fam E. Single-sperm PCR RFLP, 7% mutation-carrying sperm in fam E | Yes Aff/unaff sibs or half-sibs share same paternal haplotype with/without mutation | Fathers (two families, one bilaterally, one unilaterally affected) |
| Spinal muscular atrophy [80] One affected inheriting mutation independently from both parents, father het carrier, paternal grandmother is candidate mosaic | SMN1 Chr5 | Possibly Microsatellite genotyping showed 3 chr5 haplotypes, qPCR showed intermediate gene dosage in peripheral blood | Possibly Affected/unaffected progeny share same grandmaternal haplotype with/without mutation | Grandmother Unaffected |
| Anophthalmia syndrome [81] One severely affected, second deceased pre-term not studied | SOX2 Chr3 | Yes RFLP by DHPLC, mutant allele present with lower signal in blood, mouthwash of parent than in non-mosaic affected heterozygous offspring (qualitative) | Yes Aff/unaff sibs share same maternal haplotype with/without mutation | Mother Unaffected |
| 46,XY disorder of sexual development [82] Two fully sex-reversed XY siblings | SRY ChrY | Yes Normal and mutant SRY alleles seen for Y chromosome in peripheral blood (qualitative) | Yes Normal and mutant SRY alleles seen for Y chromosome in sperm (qualitative) | Father Unaffected |
Abbreviations: “Chr” chromosome, “Oligo” oligonucleotide, “Aff/unaff” affected/unaffected, “Fam” family, “RFLP” restriction fragment length polymorphism, “SSCP” single strang conformation polymorphism, “PAGE” polyacrylamide gel electrophoresis, “DHPLC” denaturing high performance liquid chromatography, “qPCR” quantitative polymerase chain reaction. In reports including multiple families, those families with combined somatic and germ line mutation are identified as numbered in the original publications (e.g., Rubinstein-Taybi, Duchenne muscular dystrophy). * Mutant allele frequency has a theoretical maximum of 50% in heterozygous cells (100% in cells of hemizygous non-pseudo-autosomal X or Y linked males). Some reports refer to proportion of mutation-carrying cells, with a maximum of 100%; here these are corrected to the mutant allele frequency.