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J Hum Genet. 2019 Sep;64(9):867-873. doi: 10.1038/s10038-019-0638-9. Epub 2019 Jul 8.

Four novel mutations in EFNB1 in Indian patients with craniofrontonasal syndrome.

Author information

1
Institute for Medical Genetics and Human Genetics, Charité-Universitätsmedizin Berlin, corporate member of Freie Universität Berlin, Humboldt-Universität zu Berlin, and Berlin Institute of Health, Berlin, Germany.
2
Division of Paediatric Genetics, Amrita Institute of Medical Sciences and Research Centre, Cochin, Kerala, India.
3
Division of Paediatric Neurosurgery, Amrita Institute of Medical Sciences and Research Centre, Cochin, Kerala, India.
4
Division of Craniomaxillofacial surgery, Amrita Institute of Medical Sciences and Research Centre, Cochin, Kerala, India.
5
Institute for Medical Genetics and Human Genetics, Charité-Universitätsmedizin Berlin, corporate member of Freie Universität Berlin, Humboldt-Universität zu Berlin, and Berlin Institute of Health, Berlin, Germany. uwe.kornak@charite.de.
6
Max Planck Institute for Molecular Genetics, Berlin, Germany. uwe.kornak@charite.de.
7
BIH Center for Regenerative Therapies, Charité-Universitätsmedizin Berlin, corporate member of Freie Universität Berlin, Humboldt-Universität zu Berlin, and Berlin Institute of Health, Berlin, Germany. uwe.kornak@charite.de.

Abstract

Craniofrontonasal syndrome (CFNS) (OMIM #304110) is a very rare, X-linked developmental disorder characterized by facial stigmata, including hypertelorism, frontonasal dysplasia, craniosynostosis, bifid nasal tip, and digital abnormalities. CFNS is caused by mutations in the Ephrin 1 gene (EFNB1) located at Xq13.1, which encodes the transmembrane protein Ephrin B1. Interestingly, heterozygous females are more severely affected than hemizygous males. We report on four individuals from four unrelated Indian families with mild-to-severe CFNS. All patients had variable degrees of hypertelorism and nasal bridge depression, which did not correlate with changes in other tissues. Although patients 3 and 4 showed the most severe facial dysmorphism and syndactyly, there were no structural CNS changes or developmental delay. In contrast, patient 1 displayed agenesis of corpus callosum and developmental delay, although facial and finger abnormalities were milder. Patients 1, 2, and 4 showed different degrees of clefting. DNA sequencing revealed four previously undescribed heterozygous mutations in exons 1 and 2 of EFNB1. Patient 1 carried the second single amino acid deletion reported up to date. The other three affected individuals harbored frameshift mutations, leading to premature termination codons. Our findings broaden the spectrum of EFNB1 mutations and illustrate the absence of an obvious correlation between mutation type, severity, and expression of symptoms.

PMID:
31285555
DOI:
10.1038/s10038-019-0638-9
[Indexed for MEDLINE]

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