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SCIENTIFIC SUMMARY Intellectual disability (ID) is a common impairment that affects about 3 % of the world population. Both environmental and genetic causative factors are incriminated. There is an enormous amount of literature on genetics of ID in Western countries. This contrasts with paucity of data from Africa in general and from Central Africa in particular. The prevalence of genetic defects or even the clinical presentation of African patients with a recognized syndromic cause of ID has not been systematically investigated thus far. This study aimed to contribute to the understanding of the genetic aetiology of ID in Central Africa, to gain insight into the variability in clinical expression of specific genetic disorders in Central Africa, and to gain insight into causes of and variability in genetic mutations observed in Congolese patients with a genetic disorder. This study was conducted in Kinshasa, the capital of the Democratic Republic of Congo. We collaborated with 6 institutions and recruited 127 patients including 33 (26 %) girls and 94 (74 %) boys with mean age 10.32 ± 4.68 years (range 1.24 - 24.65). After a systematic clinical examination, patients with a suspected diagnosis underwent further specific testing for that disorder. Conversely, patients without a clinical diagnosis were further studied by a genetic screening including microarray-CHG and fragile X syndrome. X-Chromosome Inactivation (XCI) pattern was studied in all available mothers of boys with ID and in all girls, thus selecting patients with a high chance of having an X-linked disorder for Whole Exome Sequencing (WES). WES was also performed in 2 affected sisters, with a suspected autosomal recessive condition. Overall, we detected a likely genetic cause in 34/127 patients (26.8 %). Down syndrome was the most frequent cause with 19 cases (14.8 %). In 10 out of 86 (11.62 %) patients with ID of clinically unknown aetiology a submicroscopic chromosomal imbalance was detected. We did not identify a single fragile X patient. Of the 41 mothers of boys with ID tested, 3 (7.32 %) (CI: 1.89 % to 18.63%) had a highly skewed X-inactivation (i.e. ≥90/10 %) and among the 27 female index patients with ID, 3 (11.11 %) had also a highly skewed X-inactivation. In one boy, a possible X-linked disorder caused by a variant in the TAF1-gene was identified after exome sequencing. In another child, we identified, by means of exome analysis, a possible autosomal recessive metabolic disorder. The majority of cases (65 %) remain without diagnosis. Several patients were clinically diagnosed with well-known conditions associated with ID, e.g. Down syndrome, Partington syndrome and Williams syndrome. The features in these conditions were very similar to those observed in the West. However, we found only a fair agreement between African and European clinicians when evaluating the facial dysmorphism in 127 Congolese patients. Likewise, when we used a recently introduced computed phenotyping program, Face2Gene for the detection of Down syndrome patients, it performed better in Caucasian (80 %) compared to Congolese patients (35 %). Therefore, ethnic background of the patient and of the physician needs to be taken into account during the evaluation of dysmorphism. The variability in clinical expression may result from environmental factors influencing the course of the disorder. One of the main differences with studies in developed countries is the environment in which Congolese children grow up. Indeed, we also found that in our cohort of patients, infections (such as meningitis) were common. However, in only few of them, an acquired brain insult was convincingly thought to be the cause of their ID. On the other hand, infections may influence the clinical manifestations, therefore one risks to overlook a genetic diagnosis, masked by an intervening environmental insult. For instance, we describe a young boy with the classical facial phenotype of Williams syndrome, caused by the recurrent 1.57 Mb deletion in chromosome 7q11.23. Surprisingly, he had severe ID and absent speech, which is most likely explained by brain damage, secondary to. meningitis and coma at age 2 years. Similarly, we diagnosed a family with X-linked congenital adrenal hypoplasia, where multiple boys died at young age due to infections. The suspicion of a genetic cause was raised when the pedigree revealed an X-linked inheritance pattern. Currently, very little is known about the causes of mutations. Advanced maternal age is the main risk factor for aneuploidies, and the advanced maternal age observed in the majority of Down syndrome cases in our cohort is in agreement with this. Advanced paternal age is a risk factor for de novo SNV’s. However, our study cannot address this question. One of the well-known mechanisms of copy number variations are unequal crossing-overs between low copy repeats (LCR). This results in recurrent, relatively common microdeletions or duplications, which share a same size (flanked by the LCR’s) and often a recognisable phenotype. Also in our study, of the 11 submicroscopic imbalances, 4 were recurrent ones. This indicates, not surprisingly, that the same mechanism also operates in the Central-African genome. Also, we report a family with Apert syndrome where a novel mutation was detected, to illustrate that genetic research in Africa can expand our knowledge on the type of mutations in well-characterized genetic disorders. The results of this study show for the first time that genetic factors are a major cause of ID in the DR Congo. Our study provides local data and insights, which will be useful for teaching and counselling. Obviously, these first results indicate the need for further expansion of similar studies. status: published |
