Familial recurrences of FOXG1‐related disorder: Evidence for mosaicism

Abstract

FOXG1-related disorders are caused by heterozygous mutations in FOXG1 and result in a spectrum of neurodevelopmental phenotypes including postnatal microcephaly, intellectual disability with absent speech, epilepsy, chorea, and corpus callosum abnormalities. The recurrence risk for de novo mutations in FOXG1-related disorders is assumed to be low. Here, we describe three unrelated sets of full siblings with mutations in FOXG1 (c.515_577del63, c.460dupG, and c.572T>G), representing familial recurrence of the disorder. In one family, we have documented maternal somatic mosaicism for the FOXG1 mutation, and all of the families presumably represent parental gonadal (or germline) mosaicism. To our knowledge, mosaicism has not been previously reported in FOXG1-related disorders. Therefore, this report provides evidence that germline mosaicism for FOXG1 mutations is a likely explanation for familial recurrence and should be considered during recurrence risk counseling for families of children with FOXG1-related disorders.

FOXG1 syndrome: genotype–phenotype association in 83 patients with FOXG1 variants

“…36 In our cohort, 5% of the families (4/76) had more than one affected child with a FOXG1 variant (excluding identical twins). In only one of three previously described families with several affected children, 3,24 maternal somatic mosaicism for the FOXG1 likely pathogenic variant was documented. 24 The parents of the patients in these families were reported as unaffected.…”

“…In only one of three previously described families with several affected children, 3,24 maternal somatic mosaicism for the FOXG1 likely pathogenic variant was documented. 24 The parents of the patients in these families were reported as unaffected. Therefore, in genetic counseling of parents of a patient with an apparent de novo variant, gonadal mosaicism needs to be considered.…”

“…Based on a Medline search, we identified additional 53 patients from 48 families with a FOXG1 variant. [1][2][3]7,9,10,14,[18][19][20][22][23][24][25][26] All available clinical, neuroimaging, and molecular data were collected from these reports and assembled with the data for the 30 new patients ( Table 1, Supplementary Table S1 online). Phenotyping had been blinded regarding retrospect assignment of FOXG1 genotype groups.…”

“…3 In eight patients from eight families, there were no data on segregation analysis in the parents. In one published family with three affected children, 3,24 maternal somatic mosaicism was reported. In four additional families (7 patients) parental gonadal mosaicism was assumed.…”

Somatic‐gonadal mosaicism causing Sotos syndrome

“…This case report demonstrates that massively parallel sequencing can detect low level somatic mosaicism and that perhaps this mechanism is the cause of some cases previously reported as gonadal mosaicism. With wider use of massively parallel sequencing, somatic‐gonadal mosaicism may emerge as an important mechanism for recurrence that can be tested in the clinical setting prior to the birth of a second affected child [Shimbo et al, ; McMahon et al, ].…”