A clustering of heterozygous missense variants in the crucial chromatin modifier WDR5 defines a new neurodevelopmental disorder.

WDR5 is a broadly studied, highly conserved key protein involved in a wide array of biological functions. Among these functions, WDR5 is a part of several protein complexes that affect gene regulation via post-translational modification of histones. We collected data from 11 unrelated individuals with six different rare de novo germline missense variants in WDR5; one identical variant was found in five individuals and another variant in two individuals. All individuals had neurodevelopmental disorders including speech/language delays (n = 11), intellectual disability (n = 9), epilepsy (n = 7), and autism spectrum disorder (n = 4). Additional phenotypic features included abnormal growth parameters (n = 7), heart anomalies (n = 2), and hearing loss (n = 2). Three-dimensional protein structures indicate that all the residues affected by these variants are located at the surface of one side of the WDR5 protein. It is predicted that five out of the six amino acid substitutions disrupt interactions of WDR5 with RbBP5 and/or KMT2A/C, as part of the COMPASS (complex proteins associated with Set1) family complexes. Our experimental approaches in Drosophila melanogaster and human cell lines show normal protein expression, localization, and protein-protein interactions for all tested variants. These results, together with the clustering of variants in a specific region of WDR5 and the absence of truncating variants so far, suggest that dominant-negative or gain-of-function mechanisms might be at play. All in all, we define a neurodevelopmental disorder associated with missense variants in WDR5 and a broad range of features. This finding highlights the important role of genes encoding COMPASS family proteins in neurodevelopmental disorders.

OEIS complex-using MRI in diagnostic: Two case reports.

OEIS complex is an acronym for a specific, extremely rare, grouping of more commonly occurring congenital malformations consisting of an omphalocele (O), exstrophy of the cloaca (E), imperforate anus (I) and spinal defects (S). It is a midline defect occurring in early blastogenesis or in mesodermal migration. The incidence is not known, it has been estimated to be 1 in 200,000-400,000 pregnancies. The etiology is thought to be heterogeneous. Most cases occur sporadically but several reports show occurrence in siblings, concurrent occurrence in monozygotic twins, and more frequent occurrence in IVF pregnancies. We report two cases of OEIS complex. Case I was recognized postnatally in twin gestation. Case II, an IVF pregnancy, was diagnosed prenatally at 35 weeks gestation by ultrasound (US) and further confirmed by magnetic resonance imaging (MRI). The purpose of this report is to present two additional cases of this rare malformation, give further evidence of the OEIS complex occurring more commonly in multiple gestations (monozygotic twins) and IVF pregnancies and illustrate the importance of MRI in prenatal diagnostics in addition to US providing better prenatal counseling, perinatal care, and planning of reconstructive surgical management.

Utility of clinical exome sequencing in a complex Emirati pediatric cohort.

Clinical exome sequencing (CES) has become a routine diagnostic tool in several pediatric subspecialties, with a reported average diagnostic yield of ~25% in this patient poulation. The utility of CES in the United Arab Emirates (UAE) has not been previously investigated, most likely due to the lack of the appropriate tertiary pediatric centers and diagnostic genomic facilities in this country. Here, we report, for the first time, CES findings on a multispecialty pediatric cohort in the UAE (N = 51). This cohort, which was mostly Emirati (86%; 44/51), was followed at Al Jalila Children's Hospital (AJCH), the first and only dedicated tertiary pediatric center in the country. CES demonstrates a high diagnostic yield (41%; 21/51) in this cohort, where 55% (28/51) had previous non-diagnostic genetic testing while for the remaining individuals (45%), CES was the first-tier test. Given the reported high consanguinity rate in this population, 48% of the positive cases (10/21) were due to genes associated with recessive conditions. However, 11 out of 21 positive cases (52%) were due to heterozygous pathogenic variants in genes known to cause dominantly inherited disorders, including a case with a dual diagnosis attributed to two different genes (2%; 1/51), and another case with a novel de novo variant and new phenotypic features for a known gene (2%; 1/51). Overall, we have identified 13 novel clinically significant variants and showed that application of CES as a first-tier test plays a significant role in genetic diagnosis and management of Emirati pediatric patients.

Cytogenomic assessment of the diagnosis of 93 patients with developmental delay and multiple congenital abnormalities: The Brazilian experience

OBJECTIVE: The human genome contains several types of variations, such as copy number variations, that can generate specific clinical abnormalities. Different techniques are used to detect these changes, and obtaining an unequivocal diagnosis is important to understand the physiopathology of the diseases. The objective of this study was to assess the diagnostic capacity of multiplex ligation-dependent probe amplification and array techniques for etiologic diagnosis of syndromic patients. METHODS: We analyzed 93 patients with developmental delay and multiple congenital abnormalities using multiplex ligation-dependent probe amplifications and arrays. RESULTS: Multiplex ligation-dependent probe amplification using different kits revealed several changes in approximately 33.3% of patients. The use of arrays with different platforms showed an approximately 53.75% detection rate for at least one pathogenic change and a 46.25% detection rate for patients with benign changes. A concomitant assessment of the two techniques showed an approximately 97.8% rate of concordance, although the results were not the same in all cases. In contrast with the array results, the MLPA technique detected ∼70.6% of pathogenic changes. CONCLUSION: The obtained results corroborated data reported in the literature, but the overall detection rate was higher than the rates previously reported, due in part to the criteria used to select patients. Although arrays are the most efficient tool for diagnosis, they are not always suitable as a first-line diagnostic approach because of their high cost for large-scale use in developing countries. Thus, clinical and laboratory interactions with skilled technicians are required to target patients for the most effective and beneficial molecular diagnosis.

Distribution of maternal age and birth order groups in cases with unclassified multiple congenital abnormalities according to the number of component abnormalities: a national population-based case-control study.

BACKGROUND: Multiple congenital abnormalities are caused by chromosomal aberrations, mutant major genes and teratogens. A minor proportion of these patients are identified as syndromes but the major part belonging to the group of unclassified multiple CAs (UMCAs). The main objective of this study was to evaluate the maternal age and birth order in pregnant women who had offspring affected with UMCA. The strong association between numerical chromosomal aberrations, e.g., Down syndrome and advanced maternal age is well-known and tested here. METHODS: The Hungarian Case-Control Surveillance of Congenital Abnormalities, 1980 to 1996, yielded a large population-based national data set with 22,843 malformed newborns or fetuses ("informative cases") included 1349 UMCA cases with their 2407 matched controls. Case-control comparison of maternal age and birth order was made for cases with UMCA, stratified by component numbers and their controls. In addition, 834 cases with Down syndrome were compared to 1432 matched controls. RESULTS: The well-known advanced maternal age with the higher risk for Down syndrome was confirmed. The findings of the study suggest that the young age of mothers associates with the higher risk of UMCA, in addition birth order 4 or more associates with the higher risk for UMCA with 2 and 3 component CAs. CONCLUSION: This study was the first to analyze the possible maternal and birth order effect for cases with UMCA, and the young age and higher birth order associated with a higher risk for UMCA.