Platelet findings in 22q11.2 deletion syndrome correlate with disease manifestations but do not correlate with GPIb surface expression.

Prior studies have demonstrated that patients with chromosome 22q11.2 deletion syndrome (22q11.2DS) have lower platelet counts (PC) compared to non-deleted populations. They also have an increased mean platelet volume. The mechanism for this has been postulated to be haploinsufficiency of the GPIBB gene. We examined platelet parameters, deletion size and factors known to influence counts, including status of thyroid hormone and congenital heart disease (CHD), in a population of 825 patients with 22q11.2DS. We also measured surface expression of GPIB-IX complex by flow cytometry. The major determinant of PC was deletion status of GP1BB, regardless of surface expression or other factors. Patients with nested distal chromosome 22q11.2 deletions (those with GP1BB present) had higher PCs than those with proximal deletions where GP1BB is deleted. Patients with 22q11.2DS also demonstrated an accelerated PC decrease with age, occurring in childhood. These data demonstrate that genes within the proximal deletion segment drive PC differences in 22q11.2DS and suggest that PC reference ranges may need to be adjusted for age and deletion size in 22q11.2DS populations. Bleeding did not correlate with either platelet count or GPIb expression. Further studies into drivers of expression of GPIb and associations with severe thrombocytopenia and immune thrombocytopenia are needed to inform clinical care.

Distinct immune trajectories in patients with chromosome 22q11.2 deletion syndrome and immune-mediated diseases.

BACKGROUND: Identification of biomarkers associated with immune-mediated diseases in 22q11.2 deletion syndrome is an evolving field. OBJECTIVES: We sought to use a carefully phenotyped cohort to study immune parameters associated with autoimmunity and atopy in 22q11.2 deletion syndrome to define biomarkers associated with immune-mediated disease in this syndrome. METHODS: Chart review validated autoimmune disease and atopic condition diagnoses. Laboratory data were extracted for each subcohort and plotted according to age. A random-effects model was used to define statistical significance. RESULTS: CD19, CD4, and CD4/45RA lymphocyte populations were not different from the general cohort for patients with atopic conditions. CD4/45RA T cells were significantly lower in the subjects with immune thrombocytopenia compared with the general cohort, and CD4 T-cell counts were lower in patients with autoimmune thyroid disease. CONCLUSIONS: The mechanisms of autoimmunity in cytopenias may be distinct from those of solid-organ autoimmunity in 22q11.2 deletion syndrome. This study identifies potential biomarkers for risk stratification among commonly obtained laboratory studies.

Cardiac evaluation of patients with 22q11.2 duplication syndrome.

The 22q11.2 duplication syndrome (22q11.2DupS) is characterized by phenotypic heterogeneity, from seemingly asymptomatic to severely affected patients. Our study sought to detail the cardiac phenotype associated with 22q11.2DupS, the prevalence of aortic arch anomalies and aortic root dilation in 22q11.2DupS, and to assess how frequently new congenital heart disease (CHD) is diagnosed at outpatient cardiac evaluation following genetic diagnosis. In our cohort of 85 patients, 20.0% had CHD, with a wide range of phenotypes. Sixty-eight patients had complete cardiac evaluations detailing aortic arch sidedness and branching pattern, of which 5 (7.4%) had an aortic arch anomaly, all of whom had concurrent intracardiac CHD. Of 53 patients without CHD who had complete cardiac evaluations, only 3 (5.7%) had evidence of aortic root dilation. Of 46 patients who underwent outpatient cardiac evaluation following diagnosis of 22q11.2DupS, only one (2.2%) was found to have CHD, an isolated bicuspid aortic valve without stenosis. Therefore, the CHD phenotype in 22q11.2DupS, when present, is heterogeneous. Aortic arch anomalies are uncommon, and no patient in our cohort had one in isolation. Isolated aortic root dilation is also uncommon. Finally, outpatient cardiac evaluation following genetic diagnosis without previously known CHD infrequently identified minor cardiac malformations.

Aortic Root Dilation in Patients with 22q11.2 Deletion Syndrome Without Intracardiac Anomalies.

Aortic root dilation (ARD) has been reported in patients with 22q11.2 deletion syndrome (22q11.2DS) with and without congenital heart defects (CHDs). However, the long-term implications of isolated ARD in 22q11.2DS remain undefined. In this study, we measured aortic root size and estimated the probability of changing between normal aortic root size and ARD during follow up to understand the prevalence, longitudinal course, and clinical risk factors for ARD in patients with 22q11.2DS without intracardiac CHDs. Aortic root size was measured in 251 patients with 432 studies. Forty-one patients (16.3%) had ARD on at least one echocardiogram and the cohort sinus Z-score was increased on the last echocardiogram [mean (1.09, SD 1.24) and median (1.20, min - 1.90 and max 5.40)]. Transition probability analysis showed that 8.1% of patients developed ARD and 45.4% of patients with ARD reverted to normal at the next echocardiogram. The risk of ARD over time was significantly associated with male sex (OR 3.06, 95% CI 1.41-6.65; p = 0.004), but not with age or presence of an aortic arch anomaly. Compared to a sinus Z-score ≥ 2, initial Z-score < 2 was associated with 14.3 times lower risk of developing sinus Z-score ≥ 3 at follow up. Sinus Z-score overall decreased by age, and males had a higher Z-score than females (ß = 0.72, SE = 0.14, p < 0.001). Though only a few patients had a Z-score > 4, and patients with initial Z-scores < 2 seem unlikely to develop clinically significant disease, screening practices remain incompletely defined such that periodic evaluation appears warranted.

What is new with 22q? An update from the 22q and You Center at the Children's Hospital of Philadelphia.

22q11.2 deletion syndrome (22q11.2DS) is a disorder caused by recurrent, chromosome-specific, low copy repeat (LCR)-mediated copy-number losses of chromosome 22q11. The Children's Hospital of Philadelphia has been involved in the clinical care of individuals with what is now known as 22q11.2DS since our initial report of the association with DiGeorge syndrome in 1982. We reviewed the medical records on our continuously growing longitudinal cohort of 1,421 patients with molecularly confirmed 22q11.2DS from 1992 to 2018. Most individuals are Caucasian and older than 8 years. The mean age at diagnosis was 3.9 years. The majority of patients (85%) had typical LCR22A-LCR22D deletions, and only 7% of these typical deletions were inherited from a parent harboring the deletion constitutionally. However, 6% of individuals harbored other nested deletions that would not be identified by traditional 22q11.2 FISH, thus requiring an orthogonal technology to diagnose. Major medical problems included immune dysfunction or allergies (77%), palatal abnormalities (67%), congenital heart disease (64%), gastrointestinal difficulties (65%), endocrine dysfunction (>50%), scoliosis (50%), renal anomalies (16%), and airway abnormalities. Median full-scale intelligence quotient was 76, with no significant difference between individuals with and without congenital heart disease or hypocalcemia. Characteristic dysmorphic facial features were present in most individuals, but dermatoglyphic patterns of our cohort are similar to normal controls. This is the largest longitudinal study of patients with 22q11.2DS, helping to further describe the condition and aid in diagnosis and management. Further surveillance will likely elucidate additional clinically relevant findings as they age.

Enhanced maternal origin of the 22q11.2 deletion in velocardiofacial and DiGeorge syndromes.

Velocardiofacial and DiGeorge syndromes, also known as 22q11.2 deletion syndrome (22q11DS), are congenital-anomaly disorders caused by a de novo hemizygous 22q11.2 deletion mediated by meiotic nonallelic homologous recombination events between low-copy repeats, also known as segmental duplications. Although previous studies exist, each was of small size, and it remains to be determined whether there are parent-of-origin biases for the de novo 22q11.2 deletion. To address this question, we genotyped a total of 389 DNA samples from 22q11DS-affected families. A total of 219 (56%) individuals with 22q11DS had maternal origin and 170 (44%) had paternal origin of the de novo deletion, which represents a statistically significant bias for maternal origin (p = 0.0151). Combined with many smaller, previous studies, 465 (57%) individuals had maternal origin and 345 (43%) had paternal origin, amounting to a ratio of 1.35 or a 35% increase in maternal compared to paternal origin (p = 0.000028). Among 1,892 probands with the de novo 22q11.2 deletion, the average maternal age at time of conception was 29.5, and this is similar to data for the general population in individual countries. Of interest, the female recombination rate in the 22q11.2 region was about 1.6-1.7 times greater than that for males, suggesting that for this region in the genome, enhanced meiotic recombination rates, as well as other as-of-yet undefined 22q11.2-specific features, could be responsible for the observed excess in maternal origin.

Hemizygous mutations in SNAP29 unmask autosomal recessive conditions and contribute to atypical findings in patients with 22q11.2DS.

BACKGROUND: 22q11.2 deletion syndrome (22q11.2DS) is the most common microdeletion disorder, affecting an estimated 1 : 2000-4000 live births. Patients with 22q11.2DS have a broad spectrum of phenotypic abnormalities which generally includes congenital cardiac abnormalities, palatal anomalies, and immunodeficiency. Additional findings, such as skeletal anomalies and autoimmune disorders, can confer significant morbidity in a subset of patients. 22q11.2DS is a contiguous gene DS and over 40 genes are deleted in patients; thus deletion of several genes within this region contributes to the clinical features. Mutations outside or on the remaining 22q11.2 allele are also known to modify the phenotype. METHODS: We utilised whole exome, targeted exome and/or Sanger sequencing to examine the genome of 17 patients with 22q11.2 deletions and phenotypic features found in <10% of affected individuals. RESULTS AND CONCLUSIONS: In four unrelated patients, we identified three novel mutations in SNAP29, the gene implicated in the autosomal recessive condition cerebral dysgenesis, neuropathy, ichthyosis and keratoderma (CEDNIK). SNAP29 maps to 22q11.2 and encodes a soluble SNARE protein that is predicted to mediate vesicle fusion at the endoplasmic reticulum or Golgi membranes. This work confirms that the phenotypic variability observed in a subset of patients with 22q11.2DS is due to mutations on the non-deleted chromosome, which leads to unmasking of autosomal recessive conditions such as CEDNIK, Kousseff, and a potentially autosomal recessive form of Opitz G/BBB syndrome. Furthermore, our work implicates SNAP29 as a major modifier of variable expressivity in 22q11.2 DS patients.

Case report: Advice for schools on managing functional tic-like behaviours.

There has been an increase in the occurrence of sudden onset functional tic-like behaviours in adolescents during the COVID-19 pandemic, which has had a significant impact on the affected individual's ability to engage with education. The aim of this article is to generate discussion and inform practice within schools with regard to the management of functional tic-like behaviours. An advice sheet for schools has been produced based on clinical expertise and experience of consulting with schools around the management within education settings. Case examples are presented highlighting the importance and impact of these strategies. We also highlight the need for further evaluation of the effectiveness of the advice sheet in collaboration with schools and families.

A novel decision aid to help plan for serious illness: a multisite randomized trial.

BACKGROUND: Recent studies have shown substantial deficiencies in the quality or quantity (or both) of communication and decision-making during serious illness. We evaluated the efficacy of a novel decision support intervention, the Plan Well Guide, in increasing completion of a standard medical order form for advance medical care planning and improving decisional outcomes in nonacademic primary care settings. METHODS: We conducted a randomized trial in 3 primary care practices in Lethbridge, Alberta in 2017-2018. We recruited "patients at high risk" referred by the primary care doctor who required establishment or review of their Goals of Care Designation (GCD). Enrolled patients were randomly allocated to receive the Plan Well Guide, delivered by a trained facilitator, or usual care. Eight to 12 weeks after the intervention, a research assistant blinded to intervention assignment contacted the patients in both groups by telephone to do a final outcome assessment. The primary outcome was completion of GCD forms; secondary outcomes included decisional conflict scores and ratings of satisfaction. RESULTS: A total of 123 patients (59 women [48.0%]; mean age 73.9 yr) were enrolled, 66 in the intervention arm and 57 in the usualcare arm; 119 patients completed the trial. After the intervention, GCD completion rates in the intervention and usual-care groups were 95.3% and 90.9%, respectively (risk difference [RD] 4%, 95% confidence interval [CI] -14% to 22%), and the rate of concordance between medical orders and expressed preferences on follow-up was 78% and 66%, respectively (RD 12%, 95% CI -7% to 30%). Significantly fewer patients in the intervention group than in the usual-care group had written medical orders for intensive care unit care and cardiopulmonary resuscitation (22 [34%] v. 33 [60%], RD -26%, 95% CI -42% to -8%). Patients in the intervention group had lower decisional conflict scores than those in the usual-care group (mean 30.9 v. 43.1, adjusted mean difference -12.0, 95% CI -23.2 to -0.8). Physicians considered patients in the intervention group to have lower decisional conflict than those in the usual-care group, although not significantly so (mean score 10.4 v. 14.9, adjusted mean difference -4.7, 95% CI -9.9 to 0.4) and spent less time with the former (mean 9.7 v. 13.2 min, adjusted mean difference -3.5, 95% CI -5.5 to -1.5 min). INTERPRETATION: The decision-support intervention did not increase GCD completion rates but did seem to improve some aspects of decisional quality while reducing the physician's time to accomplish GCD decisions. Trial registration: ClinicalTrials.gov, no. NCT01297946.

Magnetic resonance angiography (MRA) in preoperative planning for patients with 22q11.2 deletion syndrome undergoing craniofacial and otorhinolaryngologic procedures.

INTRODUCTION: Patients with 22q11.2 deletion syndrome (22q11.2DS) have a variety of anatomic anomalies. For surgeons operating in proximity to the retropharynx, the most pertinent is medial displacement of the internal carotid arteries. The purpose of this study is to describe the preoperative use of magnetic resonance angiography (MRA) in surgical planning and update the incidence rate of medial carotid displacement in patients with 22q11.2DS. METHODS: This is a retrospective cohort study of patients with a confirmed diagnosis of 22q11.2 deletion and preoperative MRA <18 years old who underwent tonsillectomy, adenoidectomy, Furlow palatoplasty (FPP), posterior pharyngeal flap (PPF), sphincter pharyngoplasty (SPP), or submucosal cleft palate (SMCP) repair between January 1st, 2008 and December 31st, 2019. RESULTS: Ninety patients who met the inclusion criteria underwent 133 procedures. The majority identified as Caucasian (84.4%); 52.2% were female. Cervical MRA was more likely to be ordered before a PPF (80.9%) and tonsillectomy (72.7%) over a FPP (47.6%) or adenoidectomy (11.1%). Carotid medialization was visualized in 23 patients (25.6%) and was mild in 11 cases, moderate in 7 cases, and significant in 5 cases. There was no association between sex, race/ethnicity, or genetic diagnosis with carotid medialization. Flap shortening was necessary in 20% of PPF cases to avoid injuring the medialized vessel. CONCLUSION: Patients with 22q11.2DS may have higher rates of medialization of the carotid arteries than previously thought. Given the risk for complications in these patients during pharyngeal operations, there may be a critical place for MRA in surgical planning for patients with 22q11.2DS.

Optical mapping of the 22q11.2DS region reveals complex repeat structures and preferred locations for non-allelic homologous recombination (NAHR).

The most prevalent microdeletion in humans occurs at 22q11.2, a region rich in chromosome-specific low copy repeats (LCR22s). The structure of this region has defied elucidation due to its size, regional complexity, and haplotype diversity, and is not well represented in the human genome reference. Most individuals with 22q11.2 deletion syndrome (22q11.2DS) carry a de novo hemizygous deletion of ~ 3 Mbp occurring by non-allelic homologous recombination (NAHR) mediated by LCR22s. In this study, optical mapping has been used to elucidate LCR22 structure and variation in 88 individuals in thirty 22q11.2DS families to uncover potential risk factors for germline rearrangements leading to 22q11.2DS offspring. Families were optically mapped to characterize LCR22 structures, NAHR locations, and genomic signatures associated with the deletion. Bioinformatics analyses revealed clear delineations between LCR22 structures in normal and deletion-containing haplotypes. Despite no explicit whole-haplotype predisposing configurations being identified, all NAHR events contain a segmental duplication encompassing FAM230 gene members suggesting preferred recombination sequences. Analysis of deletion breakpoints indicates that preferred recombinations occur between FAM230 and specific segmental duplication orientations within LCR22A and LCR22D, ultimately leading to NAHR. This work represents the most comprehensive analysis of 22q11.2DS NAHR events demonstrating completely contiguous LCR22 structures surrounding and within deletion breakpoints.

The Role of mGluR Copy Number Variation in Genetic and Environmental Forms of Syndromic Autism Spectrum Disorder.

While abnormal signaling mediated through metabotropic glutamate receptor 5 (mGluR5) is involved in the pathophysiology of Autism Spectrum Disorder (ASD), Fragile X Syndrome and Tuberous Sclerosis, the role of other mGluRs and their associated signaling network genes in syndromic ASD is unknown. This study sought to determine whether mGluR Copy Number Variants (CNV's) were overrepresented in children with syndromic ASD and if mGluR "second hit" confers additional risk for ASD in 22q11.2 Deletion Syndrome (22q11DS). To determine whether mGluR network CNV'S are enriched in syndromic ASD, we examined microarrays from children with ASD (n = 539). Patient categorization (syndromic vs nonsyndromic) was done via blinded medical chart review in mGluR positive and randomly selected mGluR negative cases. 11.5% of ASD had mGluR CNV's vs. 3.2% in controls (p < 0.001). Syndromic ASD was more prevalent in children with mGluR CNVs (74% vs 16%, p < 0.001). A comparison cohort with 22q11DS (n = 25 with ASD, n = 50 without ASD), all haploinsufficient for mGluR network gene RANBP1, were evaluated for "second mGluR hits". 20% with 22q11.2DS + ASD had "second hits" in mGluR network genes vs 2% in 22q11.2DS-ASD (p < 0.014). We propose that altered RANBP1 expression may provide a mechanistic link for several seemingly unrelated genetic and environmental forms of ASD.