Parental Somatic Mosaicism Is Underrecognized and Influences Recurrence Risk of Genomic Disorders

Abstract

New human mutations are thought to originate in germ cells, thus making a recurrence of the same mutation in a sibling exceedingly rare. However, increasing sensitivity of genomic technologies has anecdotally revealed mosaicism for mutations in somatic tissues of apparently healthy parents. Such somatically mosaic parents might also have germline mosaicism that can potentially cause unexpected intergenerational recurrences. Here, we show that somatic mosaicism for transmitted mutations among parents of children with simplex genetic disease is more common than currently appreciated. Using the sensitivity of individual-specific breakpoint PCR, we prospectively screened 100 families with children affected by genomic disorders due to rare deletion copy-number variants (CNVs) determined to be de novo by clinical analysis of parental DNA. Surprisingly, we identified four cases of low-level somatic mosaicism for the transmitted CNV in DNA isolated from parental blood. Integrated probabilistic modeling of gametogenesis developed in response to our observations predicts that mutations in parental blood increase recurrence risk substantially more than parental mutations confined to the germline. Moreover, despite the fact that maternally transmitted mutations are the minority of alleles, our model suggests that sexual dimorphisms in gametogenesis result in a greater proportion of somatically mosaic transmitting mothers who are thus at increased risk of recurrence. Therefore, somatic mosaicism together with sexual differences in gametogenesis might explain a considerable fraction of unexpected recurrences of X-linked recessive disease. Overall, our results underscore an important role for somatic mosaicism and mitotic replicative mutational mechanisms in transmission genetics.

Whole-Exome Sequencing and Whole-Genome Sequencing in Critically Ill Neonates Suspected to Have Single-Gene Disorders

“…In the context of neo-natal medicine, this would be most important for disorders related to mosaicism such as in McCune -Albright syndrome, incontinentia pigmenti, and Sturge -Weber syndrome (van den Akker et al 2009;Erickson 2010;Shirley et al 2013). Mosaicism is probably more common than previously thought, with parental germline mosaicism in singleton children with genetic diseases estimated to be at least 4% (Huisman et al 2013;Campbell et al 2014). …”

Exonic Mosaic Mutations Contribute Risk for Autism Spectrum Disorder

“…This rate is higher than what has been recently reported for de novo CNVs (4%). 22 These findings have important implications for recurrence risk and clinical testing, which are still not widely appreciated. 14,22,46,72,73 While the recurrence risk for de novo mutations is generally thought to be low ($1%), finding the presence of a mutation, even at low levels, in a parent dramatically increases this risk to a previously estimated >5%.…”

“…The mosaic nature of these mutations can make them difficult to identify with current clinical testing, even when targeting specific genes, leading to no diagnosis, misdiagnosis, or misinterpretation of recurrence risk. 16,22 It has also been hypothesized that sporadic conditions may be caused by PMMs at loci where germline mutations are embryonic lethal. 23 Importantly, when and where mutations occur in development can have a dramatic effect on the phenotypic presentation as exemplified by PIK3CA-related overgrowth spectrum (PROS).…”

Asymptomatic parental mosaicism for osteogenesis imperfecta associated with a new splice site mutation in COL1A2

“…The incidence of mosaicism is most likely highly underestimated 20. Low‐grade mosaicism is very difficult to detect by the previous traditional Sanger sequencing.…”

“…Revisions of current diagnostic laboratory protocols are needed in order to increase the detection rate of mosaic cases 21. An unknown proportion of mutations categorized as de novo may in fact result from unrecognized parental mosaicism 20. Asymptomatic parental somatic mosaicism has recently been identified by NGS and reported for a number of rare diseases such as Alport syndrome, tuberous sclerosis, and Dravet syndrome 22, 23, 24, 25.…”