Search Results (6)

The human 16p11.2 chromosomal region is rich in segmental duplications which mediate the formation of recurrent CNVs. CNVs affecting the 16p11.2 region are associated with an increased risk for developing neuropsychiatric disorders, including autism spectrum disorder (ASD), schizophrenia, and intellectual disability (ID), as well as abnormal body weight and head circumference and dysmorphic features, with marked phenotypic variability and reduced penetrance. CNVs affecting the 16p11.2 region mainly affect a distal interval of ~220 Kb, between Breakpoints 2 and 3 (BP2–BP3), and a proximal interval of ~593 Kb (BP4–BP5). Here, we report on 15 patients with recurrent 16p11.2 rearrangements that were identified among a cohort of 1600 patients (0.9%) with neurodevelopmental disorders. A total of 13 deletions and two duplications were identified, of which eight deletions included the proximal 16p11.2 region (BP4–BP5) and five included the distal 16p11.2 region (BP2–BP3). Of the two duplications that were identified, one affected the proximal and one the distal 16p11.2 region; however, both patients had additional CNVs contributing to phenotypic severity. The features observed and their severity varied greatly, even between patients within the same family. This article aims to further delineate the clinical spectrum of patients with 16p11.2 recurrent rearrangements in order to aid the counselling of patients and their families. Full article

Chromosome 4p deletions can lead to two distinct phenotypic outcomes: Wolf-–Hirschhorn syndrome (a terminal deletion at 4p16.3) and less frequently reported proximal interstitial deletions (4p11-p16). Proximal 4p interstitial deletions can result in mild to moderate intellectual disability, facial dysmorphisms, and a tall thin body habitus. To date, only 35 cases of proximal 4p interstitial deletions have been reported, and only two of these cases have been familial. The critical region for this syndrome has been narrowed down to 4p15.33-15.2, but the underlying causative genes remain unclear. In this study, we report the case of a 3-year-old female with failure to thrive, developmental and motor delays, and morphological features. The mother also had a 4p15.2-p14 deletion, and the proband was found to have a 13.4-Mb 4p15.2-p14 deletion by chromosome microarray analysis. The deleted region encompasses 16 genes, five of which have a high likelihood of contributing to the phenotype: PPARGC1A, DHX15, RBPJ, STIM2, and PCDH7. These findings suggest that multiple genes are involved in this rare proximal 4p interstitial deletion syndrome. This case highlights the need for healthcare providers to be aware of proximal 4p interstitial deletions and the potential phenotypic manifestations. Full article

The most frequent microdeletion, 22q11.2 deletion syndrome (22q11.2DS), has a wide and variable phenotype that causes difficulties in diagnosis. 22q11.2DS is a contiguous gene syndrome, but due to the existence of several low-copy-number repeat sequences (LCR) it displays a high variety of deletion types: typical deletions LCR A–D—the most common (~90%), proximal deletions LCR A–B, central deletions (LCR B, C–D) and distal deletions (LCR D–E, F). Methods: We conducted a retrospective study of 59 22q11.2SD cases, with the aim of highlighting phenotype–genotype correlations. All cases were tested using MLPA combined kits: SALSA MLPA KIT P245 and P250 (MRC Holland). Results: most cases (76%) presented classic deletion LCR A–D with various severity and phenotypic findings. A total of 14 atypical new deletions were identified: 2 proximal deletions LCR A–B, 1 CES (Cat Eye Syndrome region) to LCR B deletion, 4 nested deletions LCR B–D and 1 LCR C–D, 3 LCR A–E deletions, 1 LCR D–E, and 2 small single gene deletions: delDGCR8 and delTOP3B. Conclusions: This study emphasizes the wide phenotypic variety and incomplete penetrance of 22q11.2DS. Our findings contribute to the genotype–phenotype data regarding different types of 22q11.2 deletions and illustrate the usefulness of MLPA combined kits in 22q11.2DS diagnosis. Full article

The 22q11.2 deletion syndrome (22q11.2DS) manifests as a wide range of medical conditions across a number of systems. Pediatric growth deficiency with some catch-up growth is reported, but there are few studies of final adult height. We aimed to investigate how final adult height in 22q11.2DS compared with general population norms, and to examine predictors of short stature in in a cohort of 397 adults with 22q11.2DS (aged 17.6–76.3 years) with confirmed typical 22q11.2 microdeletion (overlapping the LCR22A to LCR22B region). We defined short stature as <3rd percentile using population norms. For the subset (n = 314, 79.1%) with 22q11.2 deletion extent, we used a binomial logistic regression model to predict short stature in 22q11.2DS, accounting for effects of sex, age, ancestry, major congenital heart disease (CHD), moderate-to-severe intellectual disability (ID), and 22q11.2 deletion extent. Adult height in 22q11.2DS showed a normal distribution but with a shift to the left, compared with population norms. Those with short stature represented 22.7% of the 22q11.2DS sample, 7.6-fold greater than population expectations (p < 0.0001). In the regression model, moderate-to-severe ID, major CHD, and the common LCR22A-LCR22D (A-D) deletion were significant independent risk factors for short stature while accounting for other factors (model p = 0.0004). The results suggest that the 22q11.2 microdeletion has a significant effect on final adult height distribution, and on short stature with effects appearing to arise from reduced gene dosage involving both the proximal and distal sub-regions of the A-D region. Future studies involving larger sample sizes with proximal nested 22q11.2 deletions, longitudinal lifetime data, parental heights, and genotype data will be valuable. Full article

Filamin C is a protein specifically expressed in myocytes and cardiomyocytes and is involved in several biological functions, including sarcomere contractile activity, signaling, cellular adhesion, and repair. FLNC variants are associated with different disorders ranging from striated muscle (myofibrillar distal or proximal) myopathy to cardiomyopathies (CMPs) (restrictive, hypertrophic, and dilated), or both. The outcome depends on functional consequences of the detected variants, which result either in FLNC haploinsufficiency or in an aberrant protein, the latter affecting sarcomere structure leading to protein aggregates. Cardiac manifestations of filaminopathies are most often described as adult onset CMPs and limited reports are available in children or on other cardiac spectrums (congenital heart defects—CHDs, or arrhythmias). Here we report on 13 variants in 14 children (2.8%) out of 500 pediatric patients with early-onset different cardiac features ranging from CMP to arrhythmias and CHDs. In one patient, we identified a deletion encompassing FLNC detected by microarray, which was overlooked by next generation sequencing. We established a potential genotype–phenotype correlation of the p.Ala1186Val variant in severe and early-onset restrictive cardiomyopathy (RCM) associated with a limb-girdle defect (two new patients in addition to the five reported in the literature). Moreover, in three patients (21%), we identified a relatively frequent finding of long QT syndrome (LQTS) associated with RCM (n = 2) and a hypertrabeculated left ventricle (n = 1). RCM and LQTS in children might represent a specific red flag for FLNC variants. Further studies are warranted in pediatric cohorts to delineate potential expanding phenotypes related to FLNC. Full article

Fanconi-Bickel syndrome (FBS) is a very rare but distinct clinical entity with the combined features of hepatic glycogen storage disease, generalized proximal renal tubular dysfunction with disproportionately severe glucosuria, and impaired galactose tolerance. Here, we report five cases (out of 93 diagnosed in our lab) with pathogenic variants on both GLUT2 (SLC2A2) alleles. They come from 3 families and presented with an exceptionally mild clinical course. This course was correlated to data from old and most recent expression and transport studies in Xenopus oocytes. GLUT2 genotype in patients 1 and 2 was p.[153_4delLI];[P417R] with the first variant exhibiting normal membrane expression and partially retained transport activity (5.8%) for 2-deoxyglucose. In patient 3, the very first GLUT2 variant ever detected (p.V197I) was found, but for the first time it was present in a patient in the homozygous state. This variant had also shown unaffected membrane expression and remarkable residual activity (8%). The genotype in patient 4, p.[153_4delLI];[(E440A)], again included the 2-amino-acid deletion with residual transporter function, and patient 5 is the first found to be homozygous for this variant. Our results provide further evidence for a genotype-phenotype correlation in patients with GLUT2 variants; non-functional variants result in the full picture of FBS while dysfunctional variants may result in milder presentations, even glucosuria only, without other typical signs of FBS. Full article