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We are all somatic postzygotic mosaics, either born that way or later as a consequence of spontaneously occurring mutations during our lifetimes. Using single‐cell whole‐genome sequencing of B lymphocytes, Zhang et al.⁸⁶⁶ found that the number of somatic mutations increases from <500 per cell in newborns to >3,000 per cell in centenarians. These dynamic changes involving other tissues as well, are likely to be associated with cancer and aging,⁸⁶⁷ and many disorders (Table 1.8).

Table 1.8 Selected examples of monogenic disorders with established somatic mosaicism with DNA confirmation.

Disorder	Gene	Reference
Achondrogenesis type 2	COL2A1	885
Aicardi–Goutières syndrome	TREX1	886
Alport syndrome	COL4A5	887
Alzheimer disease, early‐onset	PS1	888
Androgen insensitivity	AR	888
Atelostegenesis type I	FLNB	889
Beta‐propeller protein‐associated neurodegeneration	WDR45	890
Campomelic dysplasia	SOX9	888
Catecholaminergic polymorphic ventricular tachycardia	RYR2	891
Centronuclear myopathy	DNM2	892
Charcot–Marie–Tooth disease type 1E	PMP22	893
CHARGE syndrome	CHD7	888
Chronic infantile neurologic, cutaneous, articular syndrome	NLRP3	894 , 895
Chronic intestinal pseudo‐obstruction	ACTG2	864
Cleidocranial dysplasia	RUNX2	888
COL2A1 disorders	COL2A1	896
Congenital central hypoventilation syndrome	PHOX2B	897
Congenital contractural arachnodactyly	FBN2	888
Congenital disorder of glycosylation	SLC35A2	898
Congenital lipomatous overgrowth with vascular, epidermal and skeletal anomalies	PIK3CA	899
Cornelia de Lange syndrome	CdLS	900
Costello syndrome	HRAS	901
Creutzfeldt–Jakob disease	PRNP	902
Crouzon syndrome	FGFR2	903
Duchenne muscular dystrophy	DMD	888 , 904
Ectrodactyly	SHFM3	905
EEC (ectrodactyly, ectodermal dysplasia, and orofacial clefts)	P63	888
Epidermal nervus, rhabdomyosarcoma, polycystic kidneys and growth restriction	KRAS	906
Epidermolysis bullosa simplex	KRTS 5	888
Epilepsy with mental retardation in females	PCDH19	907 , 908
Facial infiltrating lipomatosis	PIK3CA	909
Familial polymicrogyria	TUBA1A	910
Fanconi anemia	FANCD2	911
Fascioscapular humeral muscular dystrophy	D4Z4	888
Freeman–Sheldon syndrome	TNNI2	912
Gardner syndrome	APC	913
Hemi‐megalencephaly	PIK3CA	914
Hemophilia A and B	F8 and F9	888
Hereditary hemorrhagic telangiectasia associated with pulmonary arterial hypertension	ACVRL1	915
Hereditary nonpolyposis colon cancer (Lynch syndrome)	MLH1	916
Hereditary spastic paraplegia	SPG4	888
Hunter syndrome	IDS	888
Hyper‐IgE syndrome	STAT3	917
Hypocalcemia	CASR	888
Infantile spinal muscular atrophy	SMN1	888
Intellectual disability	GATAD 2 B	918
Isolated growth hormone deficiency	GH1	919
Juvenile myelomonocytic leukemia	NRAS	920
Keratinocyte epidermal nevi	RAS	921
Lesch–Nyhan syndrome	HPRT1	888
Li–Fraumeni syndrome	TP53	922
Loeys–Dietz syndrome	TGFBR2	888
Lone atrial fibrillation	Cx43	923
Maffuci syndrome	IDHI	924
Marfan syndrome	FBN1	888
McCune–Albright syndrome	GNAS1	888
Metaphyseal chondromatosis with D‐2‐hydroxyglutaric aciduria	IDH1	925
MYH9 disorders	MYH9	888
Myoclonic epilepsy	SCN1A	888
Myofibrillar myopathy	BAG3	926
Myotonic dystrophy type 2	ZNF9	927
Nail–patella syndrome	LMX1B	928
Neonatal diabetes	KCNJ11	888
Neurofibromatosis type 1 (generalized and segmental)	NF1	929
Neurofibromatosis type 2	NF2	930
Ohtahara syndrome	STXBP1	931
Ollier disease	IDHI	924
Ornithine transcarbamylase deficiency	OTC	888
Osteochondromas	EXT	932
Osteogenesis imperfecta II	COL1A1, COL1A2	888
Osteopathia striata	AMER1	933
Otopalatodigital syndrome	FLNA	888
Paroxsysmal nocturnal hemoglobinuria	PIGA	888
Phenylketonuria	PAH	888
Pheochromocytomas and hemihyperplasia	UPD 11p15	934
Pitt–Hopkins syndrome	TCF4	935
Polycythemia–paraganglioma syndrome	HIF2A	936
Progeria	LMNA	937
Proteus syndrome	AKT1	938
Pseudohypoparathyroidism type 1a	GNAS	939
Pyruvate dehydrogenase complex disorder	PDHA1	940
Retinitis pigmentosa	RPGR	941
Retinoblastoma	RB1	942
Rett syndrome in males	MECP2	943
Rett syndrome, atypical	CDKL5	944
Rubinstein–Taybi syndrome	CREBBP	945 , 946
Shprintzen–Goldberg syndrome	SKI	947
Sotos syndrome	NSD1	948
Spondyloperipheral dysplasia	COL2A1	949
Stickler syndrome	COL2A1	896
Subcortical band heterotopia and pachygyria	LIS1	950
Testicular dysgenesis syndrome	SRY	951
Thanatophoric dysplasia	FGFR3	888
Timothy syndrome type 1	CACNA1C	952
Townes–Brock syndrome	SALL1	888
Uniparental disomies	–	953
Von Hippel–Lindau	VHL	888
Wiskott–Aldrich syndrome	WASP	954
X‐linked anhidrotic ectodermal dysplasia with immunodeficiency	NEMO	955
X‐linked chronic granulomatous disease	CYBB	956
X‐linked craniofrontonasal syndrome	EFNB1	957
X‐linked creatine deficiency	SLC6A8	958
X‐linked Danon disease	LAMP2	959
X‐linked dilated cardiomyopathy	DMD	960
X‐linked dyskeratosis congenita	DKC1	888
X‐linked focal dermal hypoplasia	PORCN	961 , 962
X‐linked hypophosphatemia	PHEX	888
X‐linked incontinentia pigmenti	NEMO	963
X‐linked Menkes disease	ATP7A	964
X‐linked mental retardation	ARX	888
X‐linked osteopathia striata with cranial sclerosis and developmental delay	WTX	965
X‐linked periventricular nodular heterotopia	FLNA	966
X‐linked protoporphyria	XLDPP	967
X‐linked subcortical band heterotopia	DCX	968

Somatic mosaicism has been described in almost all autosomal dominant disorders. Tissue‐ or organ‐specific segmental mosaicism explains certain overgrowth syndromes exemplified by the PIK₃CA‐associated developmental disorders that result in focal overgrowth, brain overgrowth, or capillary malformations with overgrowth.^868–870

A remarkable example of focal growth due to somatic mosaicism was the hyperinsulinism noted in an infant without any signs of the Beckwith–Wiedemann syndrome. Following removal of 80 percent of the pancreas, atypical histological features with enlarged hyperchromatic nuclei in islets were observed. Methylation analysis, a chromosomal microarray, and short tandem repeat markers led to a diagnosis of mosaic segmental paternal uniparental disomy 11p15.5‐p15.1 in pancreatic tissue, but not in the infant's blood.⁸⁷¹

Brain somatic mutations occurring during cortical development may result in sporadic intractable epilepsy.⁸⁷² One study focused on the parents of children with Dravet syndrome due to SCN1A mutations.⁸⁷³ SCN1A mosaicism was found in 5.2 percent (30 out of 575) of families with affected children. Discovery of an oncogene (e.g. RB1) for retinoblastoma occurring in the absence of a family history, will inevitably lead to examination of the parents to determine recurrence risk. An analysis using targeted deep sequencing of the parents of 124 offspring with bilateral retinoblastoma revealed only one parent with somatic mosaicism for the deleterious RB1 mutation, a 0.4 percent risk of recurrence.⁸⁷⁴

Over 700 genes are linked to neurodevelopmental disorders, some with epilepsy. Discovery of a putative de novo mutation now invariably leads to genomic evaluation of both parents in a search for somatic mosaicism. Disorders in this category include intellectual disability, epileptic encephalopathies, cerebral cortical malformations, and autism spectrum disorders.^{875, 876}

In a study of 10,362 consecutive patients, over 1 in 200 were shown to have somatic mosaicism.⁸⁷⁷ In that study, mosaicism was detected for aneuploidy, ring or marker chromosomes, microdeletion/duplication copy number variations, exonic copy number variations, and unbalanced translocations. Examples include hypomelanosis of Ito, other syndromes with patchy pigmentary abnormalities of skin associated with intellectual disability, and some patients with asymmetric growth restriction.^{878, 879} Gonadal mosaicism (see Chapter 14) should be distinguished from somatic cell mosaicism in which there is also gonadal involvement. In such cases, the patient with somatic cell mosaicism is likely to have some signs, although possibly subtle, of the disorder in question, while those with gonadal mosaicism are not expected to show any signs of the disorder. Current methodologies for clinical and prenatal diagnosis invariably list detection of very low degrees of mosaicism in a caveat that accompanies the reports. Additional examples of somatic and gonadal mosaicism include autosomal dominant osteogenesis imperfecta,^{880, 881} Huntington disease,⁸⁸² and spinocerebellar ataxia type 2.⁸⁸³ Lessons from these and the other examples quoted for gonadal mosaicism indicate a special need for caution in genetic counseling for disorders that appear to be sporadic (see Chapter 14).

Very careful examination of both parents for subtle indicators of the disorder in question is necessary, particularly in autosomal dominant and sex‐linked recessive conditions. The autosomal dominant disorders are associated with 50 percent risks of recurrence, while the sex‐linked disorders have 50 percent risk for males and 25 percent risk for recurrence in families. Pure gonadal mosaicism would likely yield risks considerably lower than these figures, such as 4–8 percent for females with gonadal mosaicism and X‐linked DMD. A second caution relating to counseling such patients with an apparent sporadic disorder is the offer of prenatal diagnosis (possibly limited) despite the inability to demonstrate the affected status of the parent.

Chromosomal mosaicism is discussed in Chapter 11 but note can be taken here of a possibly rare (and mostly undetected) autosomal trisomy. A history of subfertility with mostly mild dysmorphic features and normal intelligence has been reported in at least ten women with mosaic trisomy 18.⁸⁸⁴