stroke, psychiatric problems, cognitive impairments, and dementia. Although CADASIL is mostly adult onset, we have provided prenatal diagnosis for a family with an affected young father, as noted earlier.
Given the history of a previously affected offspring with a genetic disorder, the preconception visit serves as an ideal time to refocus on any putative diagnosis (or lack thereof), to check constantly updated databases where prior alterations are or are not considered pathogenic, and to perform newly available mutation analyses when applicable.
Recognition of genotype–phenotype associations remains challenging for reasons that include expressivity, penetrance, multiple causal genes, modifier alleles, compound heterozygosity, locus heterogeneity, interacting polymorphisms of small effect, and digenic inheritance. For the vast majority of monogenic disorders, even without known epigenetic influence (such as epilepsy, microcephaly, holoprosencephaly, hydrocephalus, craniosynostosis), definitive genotype–phenotype associations remain unknown.
Somatic mosaicism
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,
|