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Background Intellectual disability (ID) is characterised by an extreme genetic heterogeneity. Several hundred genes have been associated to monogenic forms of ID, considerably complicating molecular diagnostics. Trio-exome sequencing was recently proposed as a diagnostic approach, yet remains costly for a general implementation. Methods We report the alternative strategy of targeted high-throughput sequencing of 217 genes in which mutations had been reported in patients with ID or autism as the major clinical concern. We analysed 106 patients with ID of unknown aetiology following array-CGH analysis and other genetic investigations. Ninety per cent of these patients were males, and 75% sporadic cases. Results We identified 26 causative mutations: 16 in X-linked genes (ATRX, CUL4B, DMD, FMR1, HCFC1, IL1RAPL1, IQSEC2, KDM5C, MAOA, MECP2, SLC9A6, SLC16A2, PHF8) and 10 de novo in autosomal-dominant genes (DYRK1A, GRIN1, MED13L, TCF4, RAI1, SHANK3, SLC2A1, SYNGAP1). We also detected four possibly causative mutations (eg, in NLGN3) requiring further investigations. We present detailed reasoning for assigning causality for each mutation, and associated patients’ clinical information. Some genes were hit more than once in our cohort, suggesting they correspond to more frequent ID-associated conditions (KDM5C, MECP2, DYRK1A, TCF4). We highlight some unexpected genotype to phenotype correlations, with causative mutations being identified in genes associated to defined syndromes in patients deviating from the classic phenotype (DMD, TCF4, MECP2). We also bring additional supportive (HCFC1, MED13L) or unsupportive (SHROOM4, SRPX2) evidences for the implication of previous candidate genes or mutations in cognitive disorders. Conclusions With a diagnostic yield of 25% targeted sequencing appears relevant as a first intention test for the diagnosis of ID, but importantly will also contribute to a better understanding regarding the specific contribution of the many genes implicated in ID and autism.

Recent studies have identified suggestive prenatal features of RASopathies (e.g., increased nuchal translucency [NT], cystic hygroma [CH], hydrops, effusions, congenital heart diseases [CHD], polyhydramnios, renal anomalies). Our objective is to clarify indications for RASopathy prenatal testing. We compare genotype distributions between pre- and postnatal populations and propose genotype–phenotype correlations. Three hundred fifty-two chromosomal microarray–negative cases sent for prenatal RASopathy testing between 2012 and 2019 were collected. For most, 11 RASopathy genes were tested. Postnatal cohorts (25 patients with available prenatal information and 108 institutional database genotypes) and the NSeuroNet database were used for genotypic comparisons. The overall diagnostic yield was 14% (50/352), with rates >20% for effusions, hydrops, and CHD. Diagnostic yield was significantly improved in presence of hypertrophic cardiomyopathy (HCM), persistent or associated CH, any suggestive finding combined with renal anomaly or polyhydramnios, or ≥2 ultrasound findings. Largest prenatal contributors of pathogenic variants were PTPN11 (30%), RIT1 (16%), RAF1 (14%), and HRAS (12%), which considerably differ from their prevalence in postnatal populations. HRAS, LZTR1, and RAF1 variants correlated with hydrops/effusions, and RIT1 with prenatal onset HCM. After normal chromosomal microarray, RASopathies should be considered when any ultrasound finding of lymphatic dysplasia or suggestive CHD is found alone or in association.

Fetal anomalies represent a poorly studied group of developmental disorders. Our objective was to assess the impact of whole-exome sequencing (WES) on the investigation of these anomalies. We performed WES in 101 fetuses or stillborns who presented prenatally with severe anomalies, including renal a/dysgenesis, VACTERL association (vertebral defects, anal atresia, cardiac defects, tracheoesophageal fistula, renal anomalies, and limb abnormalities), brain anomalies, suspected ciliopathies, multiple major malformations, and akinesia. A molecular diagnosis was obtained in 19 cases (19%). In 13 of these cases, the diagnosis was not initially suspected by the clinicians because the phenotype was nonspecific or atypical, corresponding in some cases to the severe end of the spectrum of a known disease (e.g., MNX1-, RYR1-, or TUBB-related disorders). In addition, we identified likely pathogenic variants in genes (DSTYK, ACTB, and HIVEP2) previously associated with phenotypes that were substantially different from those found in our cases. Finally, we identified variants in novel candidate genes that were associated with perinatal lethality, including de novo mutations in GREB1L in two cases with bilateral renal agenesis, which represents a significant enrichment of such mutations in our cohort. Our study opens a window on the distinctive genetic landscape associated with fetal anomalies and highlights the power—but also the challenges—of WES in prenatal diagnosis.

Abstract There are more than 900 genetic syndromes associated with oral manifestations. These syndromes can have serious health implications, and left undiagnosed, can hamper treatment and prognosis later in life. About 6.67% of the population will develop a rare disease during their lifetime, some of which are difficult to diagnose. The establishment of a data and tissue bank of rare diseases with oral manifestations in Quebec will help medical professionals identify the genes involved, will improve knowledge on the rare genetic diseases, and will also lead to improved patient management. It will also allow samples and information sharing with other clinicians and investigators. As an example of a condition requiring additional research, dental ankylosis is a condition in which the tooth's cementum fuses to the surrounding alveolar bone. This can be secondary to traumatic injury but is often idiopathic, and the genes involved in the idiopathic cases, if any, are poorly known. To date, patients with both identified and unidentified genetic etiology for their dental anomalies were recruited through dental and genetics clinics for the study. They underwent sequencing of selected genes or exome sequencing depending on the manifestation. We recruited 37 patients and we identified pathogenic or likely pathogenic variants in WNT10A, EDAR, AMBN, PLOD1, TSPEAR, PRKAR1A, FAM83H, PRKACB, DLX3, DSPP, BMP2, TGDS. Our project led to the establishment of the Quebec Dental Anomalies Registry, which will help researchers, medical and dental practitioners alike understand the genetics of dental anomalies and facilitate research collaborations into improved standards of care for patients with rare dental anomalies and any accompanying genetic diseases.

Obesity is a common but highly, clinically, and genetically heterogeneous disease. Deletion of the terminal region of the short arm of chromosome 2 is rare and has been reported in about 13 patients in the literature often associated with a Prader-Willi-like phenotype. We report on five unrelated patients with 2p25 deletion of paternal origin presenting with early-onset obesity, hyperphagia, intellectual deficiency, and behavioural difficulties. Among these patients, three had de novo pure 2pter deletions, one presented with a paternal derivative der(2)t(2;15)(p25.3;q26) with deletion in the 2pter region and the last patient presented with an interstitial 2p25 deletion. The size of the deletions was characterized by SNP array or array-CGH and was confirmed by fluorescence in situ hybridization (FISH) studies. Four patients shared a 2p25.3 deletion with a minimal critical region estimated at 1.97 Mb and encompassing seven genes, namely SH3HYL1, ACP1, TMEMI8, SNTG2, TPO, PXDN, and MYT1L genes. The fifth patient had a smaller interstitial deletion encompassing the TPO, PXDN, and MYT1L genes. Paternal origin of the deletion was determined by genotyping using microsatellite markers. Analysis of the genes encompassed in the deleted region led us to speculate that the ACP1, TMEM18, and/or MYT1L genes might be involved in early-onset obesity. In addition, intellectual deficiency and behavioural troubles can be explained by the heterozygous loss of the SNTG2 and MYT1L genes. Finally, we discuss the parent-of-origin of the deletion.

The increasing use of array-CGH in malformation syndromes with intellectual disability could lead to the description of new contiguous gene syndrome by the analysis of the gene content of the microdeletion and reverse phenotyping. Thanks to a national and international call for collaboration by Achropuce and Decipher, we recruited four patients carrying de novo overlapping deletions of chromosome 9q33.3q34.11, including the STXBP1, the LMX1B and the ENG genes. We restrained the selection to these three genes because the effects of their haploinsufficency are well described in the literature and easily recognizable clinically. All deletions were detected by array-CGH and confirmed by FISH. The patients display common clinical features, including intellectual disability with epilepsy, owing to the presence of STXBP1 within the deletion, nail dysplasia and bone malformations, in particular patellar abnormalities attributed to LMX1B deletion, epistaxis and cutaneous-mucous telangiectasias explained by ENG haploinsufficiency and common facial dysmorphism. This systematic analysis of the genes comprised in the deletion allowed us to identify genes whose haploinsufficiency is expected to lead to disease manifestations and complications that require personalized follow-up, in particular for renal, eye, ear, vascular and neurological manifestations.

BackgroundThe 15q11.2 deletion is frequently identified in the neurodevelopmental clinic. Case–control studies have associated the 15q11.2 deletion with neurodevelopmental disorders, and clinical case series have attempted to delineate a microdeletion syndrome with considerable phenotypic variability. The literature on this deletion is extensive and confusing, which is a challenge for genetic counselling. The aim of this study was to estimate the effect size of the 15q11.2 deletion and quantify its contribution to neurodevelopmental disorders.MethodsWe performed meta-analyses on new and previously published case–control studies and used statistical models trained in unselected populations with cognitive assessments. We used new (n=241) and previously published (n=150) data from a clinically referred group of deletion carriers. 15q11.2 duplications (new n=179 and previously published n=35) were used as a neutral control variant.ResultsThe deletion decreases IQ by 4.3 points. The estimated ORs and respective frequencies in deletion carriers for intellectual disabilities, schizophrenia and epilepsy are 1.7 (3.4%), 1.5 (2%) and 3.1 (2.1%), respectively. There is no increased risk for heart malformations and autism. In the clinically referred group, the frequency and nature of symptoms in deletions are not different from those observed in carriers of the 15q11.2 duplication suggesting that most of the reported symptoms are due to ascertainment bias.ConclusionsWe recommend that the deletion should be classified as ‘pathogenic of mild effect size’. Since it explains only a small proportion of the phenotypic variance in carriers, it is not worth discussing in the developmental clinic or in a prenatal setting.

The Rubinstein–Taybi syndrome (RTS) is a rare autosomal-dominant disease associated with 10–15% of cases with 16p13.3 microdeletions involving the CREB-binding protein gene ( CREBBP ). We used array-comparative genomic hybridization and Quantitative multiplex fluorescent-PCR (QMF-PCR) to search for dosage anomalies in the 16p13.3 region and the CREBBP gene. We first constructed a microarray covering 2 Mb that carries seven BAC and 34 cosmid clones, as well as 26 low-molecular-weight probes (1000–1500 bp) that are spread along the CREBBP gene. To increase further the resolution inside the CREBBP gene, we used QMF-PCR assays providing a 7 kb resolution. The deletions characterized in this work extended between as little as 3.3 kb and 6.5 Mb. Some deletions were restricted to just a few exons of CREBBP , some deleted either the 5′ or the 3′ end of the gene plus adjacent genomic segments, others deleted the whole gene away. We also identified a duplication of exon 16. We showed that CREBBP dosage anomalies constitute a common cause of RTS. CREBBP high-resolution gene dosage search is therefore highly recommended for RTS diagnosis. No correlation was found between the type of deletion and the patients’ phenotype. All patients had typical RTS, and there was no particular severity associated with certain alterations.

Objective 17q12 microdeletion syndrome involves 15 genes, including HNF1B, and is considered to confer a high risk of neuropsychiatric disorders. Patients with HNF1B gene deletion diagnosed secondary to renal disorders are only very rarely reported to have neuropsychiatric disorders. Interestingly, however, when tested, patients with HNF1B gene deletion are found to have 17q12 deletion. This brings into question the extent to which 17q12 deletion is genuinely associated with severe neuropsychological disorders and in which patients. In this study, we sought to confirm 17q12 microdeletion in kidney patients initially diagnosed with HNF1B gene deletion and evaluate neuropsychological disorders in these patients compared with those with HNF1B point mutation. Patients and design Thirty-nine children with HNF1B disorders (26 with deletions) diagnosed secondary to renal abnormalities were included in this prospective study and tested for 17q12 microdeletion and neuropsychological disorders. Results The same 17q12 microdeletion found in patients with neuropsychological disorders was identified in all of our patients with HNF1B deletion. Neurological examinations found no severe impairments except for one patient with autism. No significant differences were found between patients with deletions and those with point mutations as concerns learning abilities and schooling. Nevertheless, patients with deletions tended to have lower developmental quotients and more difficulties at school. Conclusions Complete deletion of the HNF1B gene and 17q12 microdeletion syndrome are actually the same genetic disorder. The neuropsychological phenotype of patients appears less severe when 17q12 deletion is diagnosed secondary to kidney rather than neuropsychological abnormalities. These data may influence antenatal counselling.

The 2q37 locus is one of the most commonly deleted subtelomeric regions. Such a deletion has been identified in >100 patients by telomeric fluorescence in situ hybridization (FISH) analysis and, less frequently, by array-based comparative genomic hybridization (array-CGH). A recognizable '2q37-deletion syndrome' or Albright's hereditary osteodystrophy-like syndrome has been previously described. To better map the deletion and further refine this deletional syndrome, we formed a collaboration with the Association of French Language Cytogeneticists to collect 14 new intellectually deficient patients with a distal or interstitial 2q37 deletion characterized by FISH and array-CGH. Patients exhibited facial dysmorphism (13/14) and brachydactyly (10/14), associated with behavioural problems, autism or autism spectrum disorders of varying severity and overweight or obesity. The deletions in these 14 new patients measured from 2.6 to 8.8 Mb. Although the major role of HDAC4 has been demonstrated, the phenotypic involvement of several other genes in the deleted regions is unknown. We further refined the genotype-phenotype correlation for the 2q37 deletion. To do this, we examined the smallest overlapping deleted region for candidate genes for skeletal malformations (facial dysmorphism and brachydactyly), overweight, behavioural problems and seizures, using clinical data, a review of the literature, and the Manteia database. Among the candidate genes identified, we focus on the roles of PRLH, PER2, TWIST2, CAPN10, KIF1A, FARP2, D2HGDH and PDCD1.