Abstract
The introduction of whole-exome sequencing into the Pediatric Genetics clinic has increased the identification of novel genes associated with neurodevelopmental disorders and congenital anomalies. This agnostic approach has shed light on multiple proteins and pathways not previously known to be associated with disease. Here we report eight subjects from six families with predicted loss of function variants in ZNF462, a zinc-finger protein of unknown function. These individuals have overlapping phenotypes that include ptosis, metopic ridging, craniosynostosis, dysgenesis of the corpus callosum, and developmental delay. We propose that ZNF462 plays an important role in embryonic development, and is associated with craniofacial and neurodevelopmental abnormalities.
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References
Sawyer SL, Hartley T, Dyment DA et al: Utility of whole-exome sequencing for those near the end of the diagnostic odyssey: time to address gaps in care. Clin Genet 2016; 89: 275–284.
Uliana V, Percesepe A : Reverse phenotyping comes of age. Mol Genet Metab 2016; 118: 230–231.
Birgfeld CB, Saltzman BS, Hing AV et al: Making the diagnosis: metopic ridge versus metopic craniosynostosis. J Craniofac Surg 2013; 24: 178–185.
Kini U, Hurst JA, Byren JC, Wall SA, Johnson D, Wilkie AO : Etiological heterogeneity and clinical characteristics of metopic synostosis: evidence from a tertiary craniofacial unit. Am J Med Genet A 2010; 152A: 1383–1389.
Lajeunie E, Le Merrer M, Marchac D, Renier D : Syndromal and nonsyndromal primary trigonocephaly: analysis of a series of 237 patients. Am J Med Genet 1998; 75: 211–215.
Sargent C, Burn J, Baraitser M, Pembrey ME : Trigonocephaly and the Opitz C syndrome. J Med Genet 1985; 22: 39–45.
Nakane T, Kubota T, Fukushima Y, Hata Y, Ishii J, Komiyama A : Opitz trigonocephaly (C)-like syndrome, or Bohring-Opitz syndrome: another example. Am J Med Genet 2000; 92: 361–362.
Salinas-Torres VM : Say-Meyer syndrome: additional manifestations in a new patient and phenotypic assessment. Childs Nerv Syst 2015; 31: 1181–1187.
Mattina T, Perrotta CS, Grossfeld P : Jacobsen syndrome. Orphanet J Rare Dis 2009; 4: 9.
Swinkels ME, Simmons A, Smeets DF et al: Clinical and cytogenetic characterization of 13 Dutch patients with deletion 9p syndrome: delineation of the critical region for a consensus phenotype. Am J Med Genet A 2008; 146A: 1430–1438.
Hoischen A, van Bon BW, Rodriguez-Santiago B et al: De novo nonsense mutations in ASXL1 cause Bohring-Opitz syndrome. Nat Genet 2011; 43: 729–731.
Sobreira N, Schiettecatte F, Valle D, Hamosh A : GeneMatcher: a matching tool for connecting investigators with an interest in the same gene. Hum Mutat 2015; 36: 928–930.
Firth HV, Richards SM, Bevan AP et al: DECIPHER: Database of Chromosomal Imbalance and Phenotype in Humans Using Ensembl Resources. Am J Hum Genet 2009; 84: 524–533.
Firth HV, Wright CF,, D.D.D. Study: The Deciphering Developmental Disorders (DDD) study. Dev Med Child Neurol 2011; 53: 702–703.
Ramocki MB, Dowling J, Grinberg I et al: Reciprocal fusion transcripts of two novel Zn-finger genes in a female with absence of the corpus callosum, ocular colobomas and a balanced translocation between chromosomes 2p24 and 9q32. Eur J Hum Genet 2003; 11: 527–534.
Talisetti A, Forrester SR, Gregory D, Johnson L, Schneider MC, Kimonis VE : Temtamy-like syndrome associated with translocation of 2p24 and 9q32. Clin Dysmorphol 2003; 12: 175–177.
Shashi V, Pena LD, Kim K et al: De novo truncating variants in ASXL2 are associated with a unique and recognizable clinical phenotype. Am J Hum Genet 2016; 99: 991–999.
Kruszka P, Addissie YA, Yarnell CM et al: Muenke syndrome: an international multicenter natural history study. Am J Med Genet A 2016; 170A: 918–929.
Ettinger N, Williams M, Phillips JA 3rd : Variable expressivity and clinical heterogeneity can complicate the diagnosis and management of Pfeiffer syndrome. J Craniofac Surg 2013; 24: 1829–1832.
Solomon BD, Bear KA, Wyllie A et al: Genotypic and phenotypic analysis of 396 individuals with mutations in Sonic Hedgehog. J Med Genet 2012; 49: 473–479.
Franca MM, Orge AA, Carvalho LR et al: Novel heterozygous nonsense GLI2 mutations in patients with hypopituitarism and ectopic posterior pituitary lobe without holoprosencephaly. J Clin Endocrinol Metab 2010; 95: E384–E391.
Balk K, Biesecker LG : The clinical atlas of Greig cephalopolysyndactyly syndrome. Am J Med Genet A 2008; 146A: 548–557.
De Rubeis S, He X, Goldberg AP et al: Synaptic, transcriptional and chromatin genes disrupted in autism. Nature 2014; 515: 209–215.
Iossifov I, O’Roak BJ, Sanders SJ et al: The contribution of de novo coding mutations to autism spectrum disorder. Nature 2014; 515: 216–221.
Krumm N, Turner TN, Baker C et al: Excess of rare, inherited truncating mutations in autism. Nat Genet 2015; 47: 582–588.
Abrahams BS, Arking DE, Campbell DB et al: SFARI Gene 2.0: a community-driven knowledgebase for the autism spectrum disorders (ASDs). Mol Autism 2013; 4: 36.
Lek M, Karczewski KJ, Minikel EV et al: Analysis of protein-coding genetic variation in 60706 humans. Nature 2016; 536: 285–291.
Samocha KE, Robinson EB, Sanders SJ et al: A framework for the interpretation of de novo mutation in human disease. Nat Genet 2014; 46: 944–950.
Acknowledgements
We are grateful to the families for consenting to participate in this publication. We thank Dr Bård Nedregaard for his input on neuroimaging studies. The DDD study presents independent research commissioned by the Health Innovation Challenge Fund (grant number HICF-1009-003; see Nature 25533962 or www.ddduk.org/access.html for full acknowledgment). This work was supported by the intramural program of the National Human Genome Research Institute, NIH.
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Weiss, K., Wigby, K., Fannemel, M. et al. Haploinsufficiency of ZNF462 is associated with craniofacial anomalies, corpus callosum dysgenesis, ptosis, and developmental delay. Eur J Hum Genet 25, 946–951 (2017). https://doi.org/10.1038/ejhg.2017.86
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DOI: https://doi.org/10.1038/ejhg.2017.86
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