Haploinsufficiency of the Chromatin Remodeler BPTF Causes Syndromic Developmental and Speech Delay, Postnatal Microcephaly, and Dysmorphic Features.

Bromodomain PHD finger transcription factor (BPTF) is the largest subunit of nucleosome remodeling factor (NURF), a member of the ISWI chromatin-remodeling complex. However, the clinical consequences of disruption of this complex remain largely uncharacterized. BPTF is required for anterior-posterior axis formation of the mouse embryo and was shown to promote posterior neuroectodermal fate by enhancing Smad2-activated wnt8 expression in zebrafish. Here, we report eight loss-of-function and two missense variants (eight de novo and two of unknown origin) in BPTF on 17q24.2. The BPTF variants were found in unrelated individuals aged between 2.1 and 13 years, who manifest variable degrees of developmental delay/intellectual disability (10/10), speech delay (10/10), postnatal microcephaly (7/9), and dysmorphic features (9/10). Using CRISPR-Cas9 genome editing of bptf in zebrafish to induce a loss of gene function, we observed a significant reduction in head size of F0 mutants compared to control larvae. Terminal deoxynucleotidyl transferase dUTP nick end labeling (TUNEL) and phospho-histone H3 (PH3) staining to assess apoptosis and cell proliferation, respectively, showed a significant increase in cell death in F0 mutants compared to controls. Additionally, we observed a substantial increase of the ceratohyal angle of the craniofacial skeleton in bptf F0 mutants, indicating abnormal craniofacial patterning. Taken together, our data demonstrate the pathogenic role of BPTF haploinsufficiency in syndromic neurodevelopmental anomalies and extend the clinical spectrum of human disorders caused by ablation of chromatin remodeling complexes.

Perioperative glycemic measures among non-fasting gynecologic oncology patients receiving carbohydrate loading in an enhanced recovery after surgery (ERAS) protocol.

INTRODUCTION: Preoperative carbohydrate loading is an effective method to control postoperative insulin resistance. However, data are limited concerning the effects of carbohydrate loading on preoperative hyperglycemia and possible impacts on complication rates. METHODS: A prospective cohort study was performed of patients enrolled in an enhanced recovery after surgery pathway at a single institution. All patients underwent laparotomy for known or suspected gynecologic malignancies. Patients who had been diagnosed with diabetes preoperatively and those prescribed total parenteral nutrition by their providers were excluded. Data regarding preoperative carbohydrate loading with a commercial maltodextrin beverage, preoperative glucose testing, postoperative day 1 glucose, insulin administration, and complications (all complications, infectious complications, and hyperglycemia-related complications) were collected. The primary endpoint of the study was the incidence of postoperative infectious complications, defined as superficial or deep wound infection, organ/space infection, urinary tract infection, pneumonia, sepsis, or septic shock. RESULTS: Of 415 patients, 76.9% had a preoperative glucose recorded. The mean age was 60.5±12.4 years (range 18-93). Of those with recorded glucose values, 30 patients (9.4%) had glucose ≥180 mg/dL, none of whom were actually given insulin preoperatively. Median preoperative glucose value was significantly increased after carbohydrate loading (122.0 mg/dL with carbohydrate loading vs 101.0 mg/dL without, U=3143, p=0.001); however, there was no relationship between carbohydrate loading and complications. There was a significantly increased risk of hyperglycemia-related complications with postoperative day 1 morning glucose values ≥140 mg/dL (OR 1.85, 95% CI 1.07 to 3.23; p=0.03). Otherwise, preoperative and postoperative hyperglycemia with glucose thresholds of ≥140 mg/dL or ≥180 mg/dL were not associated with increased risk of other types of complications. DISCUSSION: Carbohydrate loading is associated with increased preoperative glucose values; however, this is not likely to be clinically significant as it does not have an impact on complication rates. Preoperative hyperglycemia is not a risk factor for postoperative complications in a carbohydrate-loaded population when known diabetic patients are excluded. PRECIS: While glucose increased with carbohydrate loading in non-diabetic patients, this was not associated with complications.

Clinical exome sequencing reveals locus heterogeneity and phenotypic variability of cohesinopathies.

PURPOSE: Defects in the cohesin pathway are associated with cohesinopathies, notably Cornelia de Lange syndrome (CdLS). We aimed to delineate pathogenic variants in known and candidate cohesinopathy genes from a clinical exome perspective. METHODS: We retrospectively studied patients referred for clinical exome sequencing (CES, N = 10,698). Patients with causative variants in novel or recently described cohesinopathy genes were enrolled for phenotypic characterization. RESULTS: Pathogenic or likely pathogenic single-nucleotide and insertion/deletion variants (SNVs/indels) were identified in established disease genes including NIPBL (N = 5), SMC1A (N = 14), SMC3 (N = 4), RAD21 (N = 2), and HDAC8 (N = 8). The phenotypes in this genetically defined cohort skew towards the mild end of CdLS spectrum as compared with phenotype-driven cohorts. Candidate or recently reported cohesinopathy genes were supported by de novo SNVs/indels in STAG1 (N = 3), STAG2 (N = 5), PDS5A (N = 1), and WAPL (N = 1), and one inherited SNV in PDS5A. We also identified copy-number deletions affecting STAG1 (two de novo, one of unknown inheritance) and STAG2 (one of unknown inheritance). Patients with STAG1 and STAG2 variants presented with overlapping features yet without characteristic facial features of CdLS. CONCLUSION: CES effectively identified disease-causing alleles at the mild end of the cohensinopathy spectrum and enabled characterization of candidate disease genes.

Maternal uniparental disomy of chromosome 20: a novel imprinting disorder of growth failure.

PURPOSE: Maternal uniparental disomy of chromosome 20 (UPD(20)mat) has been reported in only four patients, three of whom also had mosaicism for complete or partial trisomy of chromosome 20. We sought to evaluate the clinical significance of isolated UPD(20)mat in eight individuals. METHODS: We evaluated phenotypic and genomic findings of a series of eight new patients with UPD(20)mat. RESULTS: All eight individuals with UPD(20)mat had intrauterine growth restriction, short stature, and prominent feeding difficulties with failure to thrive. As a common feature, they often required gastric tube feeds. Genomic data in most patients are indicative of UPD as a result of trisomy rescue after meiosis II nondisjunction. CONCLUSION: We describe the first natural history of the disorder and the results of therapeutic interventions, including the frequent requirement of direct gastric feedings only during the first few years of life, and propose that growth hormone supplementation is probably safe and effective for this condition. We suggest that UPD(20)mat can be regarded as a new imprinting disorder and its identification requires specialized molecular testing, which should be performed in patients with early-onset idiopathic isolated growth failure.Genet Med 18 4, 309-315.

Novel X-linked syndrome of cardiac valvulopathy, keloid scarring, and reduced joint mobility due to filamin A substitution G1576R.

Filamin A (FLNA) is known to be involved in intracellular actin binding, cell migration, scaffolding, and signaling. We report a novel X-linked syndrome characterized by cardiac valvular disease, keloid scarring and reduced joint mobility in male second cousins due to a previously unreported mutation in FLNA. Whole exome sequencing was performed using standard methods and segregation analysis was performed in affected and non-affected family members. A novel hemizygous c.4726G>A (p.G1576R) mutation in FLNA was detected. Segregation analysis performed on multiple maternal family members showed c.4726G>A (p.G1576R) segregated with disease in an X-linked inheritance pattern. The findings in these cases are distinct from previously described FLNA related disorders by virtue of decreased joint mobility and spontaneous keloid scarring. They occur in association with a novel mutation and represent a novel genetic syndrome.

Clinical whole-exome sequencing: are we there yet?

BACKGROUND: Clinical laboratories began offering whole-exome sequencing in 2011 at a cost between $4,500 and $9,000. Reported detection rates for deleterious mutations range from 25 to 50%. Based on the experience of our clinical genetics service, actual success rates may be lower than estimated rates. We report results from our own experience along with a survey of clinical geneticists to ascertain (i) current success rates for causal gene detection in a clinical setting; (ii) if there are insurance authorization issues; and (iii) if turnaround times quoted by the clinical laboratories are accurate; we also gauge provider opinions toward clinical whole-exome sequencing. METHODS: We reviewed our results and the results of a survey that was electronically distributed to 47 clinical genetics centers. RESULTS: A total of 35 exome reports were available. If all positive results are collated, we observe a success rate of 22.8%. One result incorrectly identified a known benign variant as pathogenic. Some insurers covered all testing, whereas others denied any insurance coverage. Only three (23.1%) of our reports were available within the laboratory's quoted turnaround times. More than 50% of clinicians queried in our survey had not ordered whole-exome sequencing at the current time, many stating concerns regarding interpretation, insurance coverage, and cost. CONCLUSION: Clinical whole-exome sequencing has proven diagnostic utility; however, currently many clinicians have concerns regarding interpretation of results, insurance coverage, and cost.

Attitudes of mothers of children with down syndrome towards noninvasive prenatal testing.

Noninvasive prenatal testing (NIPT) allows for highly sensitive detection of Down syndrome early in pregnancy with no risk of miscarriage, therefore potentially increasing the number of pregnancies identified with Down syndrome. This study assesses how mothers of children with Down syndrome perceive NIPT, especially the impact they think it will have on their families and other families with children who have Down syndrome. Seventy-three self-reported mothers of children with Down syndrome responded to an anonymous online survey emailed to, and posted on, message boards of various Down syndrome support groups and networks. Data analysis included chi-square tests and thematic analysis. Fifty-nine percent of respondents indicated they would use NIPT in the future; respondents who had not used prenatal testing in the past were significantly less likely to report interest in using NIPT in the future than those who had prenatal testing previously (p < .001). Many respondents felt NIPT could lead to increased terminations (88 %), increased social stigma (57 %), and decreased availability of services for individuals with Down syndrome (64 %). However, only 16 % believed availability of new noninvasive tests would be the most important factor in determining the number of pregnancies with Down syndrome terminated in the future. Additionally, 48 % believed health care providers give biased or incorrect information about Down syndrome at the time of diagnosis, and 24 % felt this incorrect information leads to terminations of pregnancies affected with Down syndrome. Results suggest although mothers of children with Down syndrome believe new noninvasive testing will lead to an increase in termination of pregnancies with Down syndrome, they do not think it is the MOST important factor. They also highlight the need to provide a diagnosis of Down syndrome in a balanced and objective manner.

DYRK1A haploinsufficiency causes a new recognizable syndrome with microcephaly, intellectual disability, speech impairment, and distinct facies.

Dual-specificity tyrosine-(Y)-phosphorylation-regulated kinase 1 A (DYRK1A ) is a highly conserved gene located in the Down syndrome critical region. It has an important role in early development and regulation of neuronal proliferation. Microdeletions of chromosome 21q22.12q22.3 that include DYRK1A (21q22.13) are rare and only a few pathogenic single-nucleotide variants (SNVs) in the DYRK1A gene have been described, so as of yet, the landscape of DYRK1A disruptions and their associated phenotype has not been fully explored. We have identified 14 individuals with de novo heterozygous variants of DYRK1A; five with microdeletions, three with small insertions or deletions (INDELs) and six with deleterious SNVs. The analysis of our cohort and comparison with published cases reveals that phenotypes are consistent among individuals with the 21q22.12q22.3 microdeletion and those with translocation, SNVs, or INDELs within DYRK1A. All individuals shared congenital microcephaly at birth, intellectual disability, developmental delay, severe speech impairment, short stature, and distinct facial features. The severity of the microcephaly varied from -2 SD to -5 SD. Seizures, structural brain abnormalities, eye defects, ataxia/broad-based gait, intrauterine growth restriction, minor skeletal abnormalities, and feeding difficulties were present in two-thirds of all affected individuals. Our study demonstrates that haploinsufficiency of DYRK1A results in a new recognizable syndrome, which should be considered in individuals with Angelman syndrome-like features and distinct facial features. Our report represents the largest cohort of individuals with DYRK1A disruptions to date, and is the first attempt to define consistent genotype-phenotype correlations among subjects with 21q22.13 microdeletions and DYRK1A SNVs or small INDELs.