Abstract
Heterozygous disruptions in FOXP1 are responsible for developmental delay, intellectual disability and speech deficit. Heterozygous germline PTCH1 disease-causing variants cause Gorlin syndrome. We describe a girl with extreme megalencephaly, developmental delay and severe intellectual disability. Dysmorphic features included prominent forehead, frontal hair upsweep, flat, wide nasal bridge, low-set, abnormally modelled ears and post-axial cutaneous appendages on the hands. Brain MRI showed partial agenesis of the corpus callosum and widely separated leaves of the septum pellucidum. Exome sequencing of a gene set representing a total of 4813 genes with known relationships to human diseases revealed an already known heterozygous de novo nonsense disease-causing variant in FOXP1 (c.1573C>T, p.Arg525Ter) and a heterozygous novel de novo frameshift nonsense variant in PTCH1 (c.2834delGinsAGATGTTGTGGACCC, p.Arg945GlnfsTer22). The composite phenotype of the patient seems to be the result of two monogenic diseases, although more severe than described in conditions due to disease-causing variants in either gene.
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References
Golson ML, Kaestner KH. Fox transcription factors: from development to disease. Development. 2016;143:4558–70.
Hamdan FF, Daoud H, Rochefort D, Piton A, Gauthier J, Langlois M, et al. De novo mutations in FOXP1 in cases with intellectual disability, autism, and language impairment. Am J Hum Genet. 2010;87:671–8.
Le Fevre AK, Tylor S, Malek NH, Horn D, Carr CW, Abdul-Rahman OA, et al. FOXP1 mutations cause intellectual disability and a recognizable phenotype. Am J Med Genet A. 2013;161A:3166–75.
Meerschaut I, Rochefort D, Revençu N, Pètre J, Corsello C, Rouleau GA, et al. FOXP1-related intellectual disability syndrome: a recognisable entity. J Med Genet. 2017;54:613–23.
Siper PM, De Rubeis S, del Pilar Trelles M, Durkin A, Di Marino D, Muratet F, et al. Prospective investigation of FOXP1 syndrome. Mol Autism. 2017;8:57.
Lindström E, Shimokawa T, Toftgård R, Zaphiropoulos PG. PTCH mutations: distribution and analyses. Hum Mutat. 2006;27:215–9.
Reinders MG, van Hout AF, Cosgun B, Paulussen AD, Leter EM, Steijlen PM. et al. New mutations and an updated database for the patched-1 (PTCH1) gene. Mol Genet Genomic Med. 2018;6:409–15.
Fujii K, Miyashita T. Gorlin syndrome (nevoid basal cell carcinoma syndrome): update and literature review. Pediatr Intern. 2014;56:667–74.
Mirzaa GM, Poduri A. Megalencephaly and hemimegalencephaly: breakthroughs in molecular etiology. Am J Med Genet C. 2014;166C:156–72.
Kimonis VE, Goldstein AM, Pastakia B, Yang ML, Kase R, DiGiovanna JJ, et al. Clinical manifestations in 105 persons with nevoid basal cell carcinoma syndrome. Am J Med Genet. 1997;69:299–308.
Kimonis VE, Mehta SG, DiGiovanna JJ, Bale SJ, Pastakia B. Radiological features in 82 patients with nevoid basal cell carcinoma (NBCC or Gorlin) syndrome. Genet Med. 2004;6:495–502.
Kimonis VE, Singh KE, Zhong R, Pastakia B, DiGiovanna JJ, Bale SJ. Clinical and radiological features in young individuals with nevoid basal cell carcinoma syndrome. Genet Med. 2013;15:79–83.
Veenstra-Knol HE, Scheewe JH, van der Vlist GJ, van Doorn ME, Ausems MGEM. Early recognition of basal cell naevus syndrome. Eur J Pediatr. 2005;164:126–30.
Shiohama T, Fujii K, Miyashita T, Mizuochi H, Uchikawa H, Shimojo N. Brain morphology in children with nevoid basal cell carcinoma syndrome. Am J Med Genet. 2017;173:946–52.
Sollis E, Graham SA, Vino A, Froehlich H, Vreeburg M, Dimitropoulou D, et al. Identification and functional characterization of de novo FOXP1 variants provides novel insights into the etiology of neurodevelopmental disorder. Hum Mol Genet. 2016;25:546–57.
Estruch SB, Graham SA, Quevedo M, Vino A, Dekkers DHW, Deriziotis P, et al. Proteomic analysis of FOXP proteins reveals interactions between cortical transcription factors associated with neurodevelopmental disorders. Hum Mol Genet. 2018;27:1212–27.
Braccioli L, Vervoort SJ, Adolfs Y, Heijnen CJ, Basak O, Pasterkamp RJ, et al. FOXP1 promotes embryonic neural stem cell differentiation by repressing Jagged1 expression. Stem Cell Rep. 2017;9:1530–45.
Li X, Xiao J, Fröhlich H, Tu X, Li L, Xu Y, et al. Foxp1 regulates cortical radial migration and neuronal morphogenesis in developing cerebral cortex. PLoS ONE. 2015;10:e0127671.
Usui N, Araujo DJ, Kulkarni A, Co M, Ellegood J, Harper M, et al. Foxp1 regulation of neonatal vocalizations via cortical development. Genes Dev. 2017;31:2039–55.
Briscoe J, Thérond PP. The mechanism of Hedgehog signalling and its roles in development and disease. Nat Rev Mol Cell Biol. 2013;14:416–29.
Acknowledgements
We thank the members of the patient’s family for their cooperation.
Funding
This study was supported by the GINOP-2.3.2-15-2 grant (to TK and ZM) provided by the National Research, Development and Innovation Office (Hungary).
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Written informed parental consent has been obtained. The study was approved by the Human Investigation Review Board at Albert Szent-Györgyi Clinical Centre, University of Szeged, Hungary.
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The authors declare that they have no conflict of interest.
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Zombor, M., Kalmár, T., Maróti, Z. et al. Co-occurrence of mutations in FOXP1 and PTCH1 in a girl with extreme megalencephaly, callosal dysgenesis and profound intellectual disability. J Hum Genet 63, 1189–1193 (2018). https://doi.org/10.1038/s10038-018-0508-x
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DOI: https://doi.org/10.1038/s10038-018-0508-x
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