Abstract
Truncating ASXL3 mutations were first identified in 2013 by Bainbridge et al. as a cause of syndromic intellectual disability in four children with similar phenotypes using whole-exome sequencing. The clinical features – postulated by Bainbridge et al. to be overlapping with Bohring–Opitz syndrome – were developmental delay, severe feeding difficulties, failure to thrive and neurological abnormalities. This condition was included in OMIM as ‘Bainbridge–Ropers syndrome’ (BRPS, #615485). To date, a total of nine individuals with BRPS have been published in the literature in four reports (Bainbridge et al., Dinwiddie et al, Srivastava et al. and Hori et al.). In this report, we describe six unrelated patients with newly diagnosed heterozygous de novo loss-of-function variants in ASXL3 and concordant clinical features: severe muscular hypotonia with feeding difficulties in infancy, significant motor delay, profound speech impairment, intellectual disability and a characteristic craniofacial phenotype (long face, arched eyebrows with mild synophrys, downslanting palpebral fissures, prominent columella, small alae nasi, high, narrow palate and relatively little facial expression). The majority of key features characteristic for Bohring–Opitz syndrome were absent in our patients (eg, the typical posture of arms, intrauterine growth retardation, microcephaly, trigonocephaly, typical facial gestalt with nevus flammeus of the forehead and exophthalmos). Therefore we emphasize that BRPS syndrome, caused by ASXL3 loss-of-function variants, is a clinically distinct intellectual disability syndrome with a recognizable phenotype distinguishable from that of Bohring–Opitz syndrome.
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Acknowledgements
We are grateful to the patients and their families for participating in this study and for giving consent to publish data and photographs. We thank Sabine Kaya and Daniela Falkenstein for excellent technical assistance. Parts of this study were supported by a grant from the Interdisciplinary Center for Clinical Research (laboratory rotation) of the Clinical Center Erlangen of the Friedrich-Alexander-Universität Erlangen-Nürnberg (to UH), the German Ministry of Research and Education (grant numbers 01GS08164, 01GS08167, 01GS08163, German Mental Retardation Network) as part of the National Genome Research Network (to HE), the German Network for Mitochondrial Disorders (mitoNET; 01GM1113 to HP), the E-Rare project GENOMIT (01GM1207 to HP) and the Juniorverbund in der Systemmedizin 'mitOmics' (FKZ 01ZX1405C to TBH). We thank the PARI 2012 Marfanoid habitus and intellectual deficiency (Regional Council of Burgundy and Dijon University Hospital, France) for its financial support.
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Kuechler, A., Czeschik, J., Graf, E. et al. Bainbridge–Ropers syndrome caused by loss-of-function variants in ASXL3: a recognizable condition. Eur J Hum Genet 25, 183–191 (2017). https://doi.org/10.1038/ejhg.2016.165
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DOI: https://doi.org/10.1038/ejhg.2016.165
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