Cornelia de Lange syndrome in diverse populations

Leah Dowsett, Antonio R Porras, Paul Kruszka, Brandon Davis, Tommy Hu, Engela Honey, Eben Badoe, Meow-Keong Thong, Eyby Leon, Katta M Girisha, Anju Shukla, Shalini S Nayak, Vorasuk Shotelersuk, Andre Megarbane, Shubha Phadke, Nirmala D Sirisena, Vajira H W Dissanayake, Carlos R Ferreira, Monisha S Kisling, Pranoot Tanpaiboon, Annette Uwineza, Leon Mutesa, Cedrik Tekendo-Ngongang, Ambroise Wonkam, Karen Fieggen, Leticia Cassimiro Batista, Danilo Moretti-Ferreira, Roger E Stevenson, Eloise J Prijoles, David Everman, Kate Clarkson, Jessica Worthington, Virginia Kimonis, Fuki Hisama, Carol Crowe, Paul Wong, Kisha Johnson, Robin D Clark, Lynne Bird, Diane Masser-Frye, Marie McDonald, Patrick Willems, Elizabeth Roeder, Sulgana Saitta, Kwame Anyane-Yeoba, Laurie Demmer, Naoki Hamajima, Zornitza Stark, Greta Gillies, Louanne Hudgins, Usha Dave, Stavit Shalev, Victoria Siu, Ann Ades, Holly Dubbs, Sarah Raible, Maninder Kaur, Emanuela Salzano, Laird Jackson, Matthew Deardorff, Antonie Kline, Marshall Summar, Maximilian Muenke, Marius George Linguraru, Ian D Krantz
American Journal of Medical Genetics. Part A 2019, 179 (2): 150-158
Cornelia de Lange syndrome (CdLS) is a dominant multisystemic malformation syndrome due to mutations in five genes-NIPBL, SMC1A, HDAC8, SMC3, and RAD21. The characteristic facial dysmorphisms include microcephaly, arched eyebrows, synophrys, short nose with depressed bridge and anteverted nares, long philtrum, thin lips, micrognathia, and hypertrichosis. Most affected individuals have intellectual disability, growth deficiency, and upper limb anomalies. This study looked at individuals from diverse populations with both clinical and molecularly confirmed diagnoses of CdLS by facial analysis technology. Clinical data and images from 246 individuals with CdLS were obtained from 15 countries. This cohort included 49% female patients and ages ranged from infancy to 37 years. Individuals were grouped into ancestry categories of African descent, Asian, Latin American, Middle Eastern, and Caucasian. Across these populations, 14 features showed a statistically significant difference. The most common facial features found in all ancestry groups included synophrys, short nose with anteverted nares, and a long philtrum with thin vermillion of the upper lip. Using facial analysis technology we compared 246 individuals with CdLS to 246 gender/age matched controls and found that sensitivity was equal or greater than 95% for all groups. Specificity was equal or greater than 91%. In conclusion, we present consistent clinical findings from global populations with CdLS while demonstrating how facial analysis technology can be a tool to support accurate diagnoses in the clinical setting. This work, along with prior studies in this arena, will assist in earlier detection, recognition, and treatment of CdLS worldwide.

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