The evaluation of facial dysmorphism is a critical step toward reaching a diagnostic. The aim of the present study was to evaluate the ability to interpret facial morphology in African children with intellectual disability (ID). First, 10 experienced clinicians (five from Africa and five from Europe) rated gestalt in 127 African non-Down Syndrome (non-DS) patients using either the score 2 for 'clearly dysmorphic', 0 for 'clearly non dysmorphic' or 1 for 'uncertain'. The inter-rater agreement was determined using kappa coefficient. There was only fair agreement between African and European raters (kappa-coefficient = 0.29). Second, we applied the FDNA Face2Gene solution to assess Down Syndrome (DS) faces. Initially, Face2Gene showed a better recognition rate for DS in Caucasian (80%) compared to African (36.8%). We trained the Face2Gene with a set of African DS and non-DS photographs. Interestingly, the recognition in African increased to 94.7%. Thus, training improved the sensitivity of Face2Gene. Our data suggest that human based evaluation is influenced by ethnic background of the evaluator. In addition, computer based evaluation indicates that the ethnic of the patient also influences the evaluation and that training may increase the detection specificity for a particular ethnic.

We would like to thank the families for their participation to this study and the members of both the MAIA (http://www.maia-asso.org) and Syndrome de Rokitansky-MRKH (http://asso.orpha.net/MRKH) associations for their contribution. We are also indebted to the physicians involved in the French national PRAM network (Programme de Recherches sur les Aplasies Müllériennes), the GACUA and the GARD research programs. We thank the GIGA Genomics Platform for technical assistance with NGS data generation. This research was supported by funding from the CHU Liège (FIRS), the Walloon Region (WALGEMED project), the University of Liège and the Fond Léon Frédéricq. AJ is supported by the National Fund for Scientific Research, Belgium. Conflict of Interest statementThe authors declare that they have no conflict of interest. Ethics approvalThe GARD (genetic alterations in rare diseases) protocol was approved by the UBC Children's and Women's Research Ethics Board (Vancouver, Canada). The GACUA (Identification of genetic factors involved in uterine development by exome sequencing of individuals with hereditary or syndromic uterine and kidney malformation) protocol was approved by the ethics committee from the University Hospital and the University of Liège, Belgium. The PRAM project was approved by the local institutional review board (Comité de Protection des Personnes), and is registered with the French Ministry of Health. The procedures used in this study adhere to the tenets of the Declaration of Helsinki.

The rich and diverse genomics of African populations is significantly underrepresented in reference and in disease-associated databases. This renders interpreting the Next Generation Sequencing (NGS) data and reaching a diagnostic more difficult in Africa and for the African diaspora. It increases chances for false positives with variants being misclassified as pathogenic due to their novelty or rarity. We can increase African genomic data by (1) making consent for sharing aggregate frequency data an essential component of research toolkit; (2) encouraging investigators with African data to share available data through public resources such as gnomAD, AVGD, ClinVar, DECIPHER and to use MatchMaker Exchange; (3) educating African research participants on the meaning and value of sharing aggregate frequency data; and (4) increasing funding to scale-up the production of African genomic data that will be more representative of the geographical and ethno-linguistic variation on the continent. The RDWG of H3Africa is hereby calling to action because this underrepresentation accentuates the health disparities. Applying the NGS to shorten the diagnostic odyssey or to guide therapeutic options for rare diseases will fully work for Africans only when public repositories include sufficient data from African subjects.

Deletions in chromosome 14q22-23 have been associated with variable manifestations including malformations of the eye, limbs, palate, and brain, and with developmental and growth delay. Haploinsufficiency of BMP4, OTX2 and possibly SIX6 are thought to contribute to the phenotype. We present a three generation family with four individuals carrying a 2.79 Mb microdeletion 14q22.1-22.2 encompassing BMP4 but not OTX2 nor SIX6. The highly variable manifestations in this family range from multiple congenital malformations with Robin sequence, microphthalmia, postaxial polydactyly, and developmental delay in the index patient to cleft uvula, growth delay, and mild developmental delay in her sister. The adults have a normal intelligence, postaxial polydactyly, and short stature or early cataract. Genotype-phenotype correlations suggest that the severity of eye manifestations in 14q22 deletions are influenced by the size of the deletion, but the marked intrafamilial variability observed in this family, as well as in familial BMP4 or OTX2 intragenic mutations points to additional modifiers outside this region.