Familial Recurrences of FOXG1-related Disorder: Evidence for Mosaicism

Overview

Journal Am J Med Genet A

Specialty Genetics

Date 2015 Sep 15

PMID 26364767

Citations 13

Authors

Kelly Q McMahon

Apostolos Papandreou

Mandy Ma

Brenda J Barry

Ghayda M Mirzaa

William B Dobyns

Richard H Scott

Natalie Trump

Manju A Kurian

Alex R Paciorkowski

Affiliations

Soon will be listed here.

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.

Citing Articles

PLP1-Targeting Antisense Oligonucleotides Improve FOXG1 Syndrome Mice.

Tan D, Jung S, Deng Y, Morey N, Chan G, Bongers A Int J Mol Sci. 2024; 25(19).

PMID: 39409184 PMC: 11477415. DOI: 10.3390/ijms251910846.

The postnatal injection of AAV9-FOXG1 rescues corpus callosum agenesis and other brain deficits in the mouse model of FOXG1 syndrome.

Jeon S, Park J, Likhite S, Moon J, Shin D, Li L Mol Ther Methods Clin Dev. 2024; 32(3):101275.

PMID: 39022742 PMC: 11253142. DOI: 10.1016/j.omtm.2024.101275.

Gastrointestinal Dysfunction in Genetically Defined Neurodevelopmental Disorders.

Davidson E, Holingue C, Jimenez-Gomez A, Dallman J, Moshiree B Semin Neurol. 2023; 43(4):645-660.

PMID: 37586397 PMC: 10895389. DOI: 10.1055/s-0043-1771460.

Identification of a mutation of the gene and comprehensive analysis for molecular factors in Chinese FOXG1-related encephalopathies.

Lu G, Zhang Y, Xia H, He X, Xu P, Wu L Front Mol Neurosci. 2022; 15:1039990.

PMID: 36568277 PMC: 9768341. DOI: 10.3389/fnmol.2022.1039990.

The Gut-Brain-Microbiome Axis and Its Link to Autism: Emerging Insights and the Potential of Zebrafish Models.

James D, Davidson E, Yanes J, Moshiree B, Dallman J Front Cell Dev Biol. 2021; 9:662916.

PMID: 33937265 PMC: 8081961. DOI: 10.3389/fcell.2021.662916.

References

Tohyama J, Yamamoto T, Hosoki K, Nagasaki K, Akasaka N, Ohashi T . West syndrome associated with mosaic duplication of FOXG1 in a patient with maternal uniparental disomy of chromosome 14. Am J Med Genet A. 2011; 155A(10):2584-8. DOI: 10.1002/ajmg.a.34224. View

Hall J . Review and hypotheses: somatic mosaicism: observations related to clinical genetics. Am J Hum Genet. 1988; 43(4):355-63. PMC: 1715487. View

Wijsman E . Recurrence risk of a new dominant mutation in children of unaffected parents. Am J Hum Genet. 1991; 48(4):654-61. PMC: 1682956. View

Papa F, Mencarelli M, Caselli R, Katzaki E, Sampieri K, Meloni I . A 3 Mb deletion in 14q12 causes severe mental retardation, mild facial dysmorphisms and Rett-like features. Am J Med Genet A. 2008; 146A(15):1994-8. DOI: 10.1002/ajmg.a.32413. View

van der Meulen M, van der Meulen M, Te Meerman G . Recurrence risk for germinal mosaics revisited. J Med Genet. 1995; 32(2):102-4. PMC: 1050228. DOI: 10.1136/jmg.32.2.102. View

Campbell I, Stewart J, James R, Lupski J, Stankiewicz P, Olofsson P . Parent of origin, mosaicism, and recurrence risk: probabilistic modeling explains the broken symmetry of transmission genetics. Am J Hum Genet. 2014; 95(4):345-59. PMC: 4185125. DOI: 10.1016/j.ajhg.2014.08.010. View

EMERY A . Risk estimation in autosomal dominant disorders with reduced penetrance. J Med Genet. 1986; 23(4):316-8. PMC: 1049696. DOI: 10.1136/jmg.23.4.316. View

Florian C, Bahi-Buisson N, Bienvenu T . FOXG1-Related Disorders: From Clinical Description to Molecular Genetics. Mol Syndromol. 2012; 2(3-5):153-163. PMC: 3366704. DOI: 10.1159/000327329. View

Mencarelli M, Spanhol-Rosseto A, Artuso R, Rondinella D, de Filippis R, Bahi-Buisson N . Novel FOXG1 mutations associated with the congenital variant of Rett syndrome. J Med Genet. 2009; 47(1):49-53. DOI: 10.1136/jmg.2009.067884. View

10.

Ariani F, Hayek G, Rondinella D, Artuso R, Mencarelli M, Spanhol-Rosseto A . FOXG1 is responsible for the congenital variant of Rett syndrome. Am J Hum Genet. 2008; 83(1):89-93. PMC: 2443837. DOI: 10.1016/j.ajhg.2008.05.015. View

11.

Martynoga B, Morrison H, Price D, Mason J . Foxg1 is required for specification of ventral telencephalon and region-specific regulation of dorsal telencephalic precursor proliferation and apoptosis. Dev Biol. 2005; 283(1):113-27. DOI: 10.1016/j.ydbio.2005.04.005. View

12.

Striano P, Paravidino R, Sicca F, Chiurazzi P, Gimelli S, Coppola A . West syndrome associated with 14q12 duplications harboring FOXG1. Neurology. 2011; 76(18):1600-2. DOI: 10.1212/WNL.0b013e3182194bbf. View

13.

Bertossi C, Cassina M, De Palma L, Vecchi M, Rossato S, Toldo I . 14q12 duplication including FOXG1: is there a common age-dependent epileptic phenotype?. Brain Dev. 2013; 36(5):402-7. DOI: 10.1016/j.braindev.2013.06.008. View

14.

CHANDLEY A . On the parental origin of de novo mutation in man. J Med Genet. 1991; 28(4):217-23. PMC: 1016821. DOI: 10.1136/jmg.28.4.217. View

15.

Brunetti-Pierri N, Paciorkowski A, Ciccone R, Mina E, Bonaglia M, Borgatti R . Duplications of FOXG1 in 14q12 are associated with developmental epilepsy, mental retardation, and severe speech impairment. Eur J Hum Genet. 2010; 19(1):102-7. PMC: 3039509. DOI: 10.1038/ejhg.2010.142. View

16.

Bahi-Buisson N, Nectoux J, Girard B, Van Esch H, de Ravel T, Boddaert N . Revisiting the phenotype associated with FOXG1 mutations: two novel cases of congenital Rett variant. Neurogenetics. 2009; 11(2):241-9. DOI: 10.1007/s10048-009-0220-2. View

17.

Le Guen T, Bahi-Buisson N, Nectoux J, Boddaert N, Fichou Y, Diebold B . A FOXG1 mutation in a boy with congenital variant of Rett syndrome. Neurogenetics. 2010; 12(1):1-8. DOI: 10.1007/s10048-010-0255-4. View

18.

Lazaro C, Ravella A, Gaona A, Volpini V, Estivill X . Neurofibromatosis type 1 due to germ-line mosaicism in a clinically normal father. N Engl J Med. 1994; 331(21):1403-7. DOI: 10.1056/NEJM199411243312102. View

19.

Hartl D . Recurrence risks for germinal mosaics. Am J Hum Genet. 1971; 23(2):124-34. PMC: 1706682. View

20.

Jacob F, Ramaswamy V, Andersen J, Bolduc F . Atypical Rett syndrome with selective FOXG1 deletion detected by comparative genomic hybridization: case report and review of literature. Eur J Hum Genet. 2009; 17(12):1577-81. PMC: 2987032. DOI: 10.1038/ejhg.2009.95. View