ClinGen variant curation expert panel recommendations for classification of variants in GAMT, GATM and SLC6A8 for cerebral creatine deficiency syndromes.

Cerebral creatine deficiency syndromes (CCDS) are inherited metabolic phenotypes of creatine synthesis and transport. There are two enzyme deficiencies, guanidinoacetate methyltransferase (GAMT), encoded by GAMT and arginine-glycine amidinotransferase (AGAT), encoded by GATM, which are involved in the synthesis of creatine. After synthesis, creatine is taken up by a sodium-dependent membrane bound creatine transporter (CRTR), encoded by SLC6A8, into all organs. Creatine uptake is very important especially in high energy demanding organs such as the brain, and muscle. To classify the pathogenicity of variants in GAMT, GATM, and SLC6A8, we developed the CCDS Variant Curation Expert Panel (VCEP) in 2018, supported by The Clinical Genome Resource (ClinGen), a National Institutes of Health (NIH)-funded resource. We developed disease-specific variant classification guidelines for GAMT-, GATM-, and SLC6A8-related CCDS, adapted from the American College of Medical Genetics/Association of Molecular Pathology (ACMG/AMP) variant interpretation guidelines. We applied specific variant classification guidelines to 30 pilot variants in each of the three genes that have variants associated with CCDS. Our CCDS VCEP was approved by the ClinGen Sequence Variant Interpretation Working Group (SVI WG) and Clinical Domain Oversight Committee in July 2022. We curated 181 variants including 72 variants in GAMT, 45 variants in GATM, and 64 variants in SLC6A8 and submitted these classifications to ClinVar, a public variant database supported by the National Center for Biotechnology Information. Missense variants were the most common variant type in all three genes. We submitted 32 new variants and reclassified 34 variants with conflicting interpretations. We report specific phenotype (PP4) using a points system based on the urine and plasma guanidinoacetate and creatine levels, brain magnetic resonance spectroscopy (MRS) creatine level, and enzyme activity or creatine uptake in fibroblasts ranging from PP4, PP4_Moderate and PP4_Strong. Our CCDS VCEP is one of the first panels applying disease specific variant classification algorithms for an X-linked disease. The availability of these guidelines and classifications can guide molecular genetics and genomic laboratories and health care providers to assess the molecular diagnosis of individuals with a CCDS phenotype.

Evaluating the strength of evidence for genes implicated in peroxisomal disorders using the ClinGen clinical validity framework and providing updates to the peroxisomal disease nomenclature.

Peroxisomal disorders are heterogeneous in nature, with phenotypic overlap that is indistinguishable without molecular testing. Newborn screening and gene sequencing for a panel of genes implicated in peroxisomal diseases are critical tools for the early and accurate detection of these disorders. It is therefore essential to evaluate the clinical validity of the genes included in sequencing panels for peroxisomal disorders. The Peroxisomal Gene Curation Expert Panel (GCEP) assessed genes frequently included on clinical peroxisomal testing panels using the Clinical Genome Resource (ClinGen) gene-disease validity curation framework and classified gene-disease relationships as Definitive, Strong, Moderate, Limited, Disputed, Refuted, or No Known Disease Relationship. Subsequent to gene curation, the GCEP made recommendations to update the disease nomenclature and ontology in the Monarch Disease Ontology (Mondo) database. Thirty-six genes were assessed for the strength of evidence supporting their role in peroxisomal disease, leading to 36 gene-disease relationships, after two genes were removed for their lack of a role in peroxisomal disease and two genes were curated for two different disease entities each. Of these, 23 were classified as Definitive (64%), one as Strong (3%), eight as Moderate (23%), two as Limited (5%), and two as No known disease relationship (5%). No contradictory evidence was found to classify any relationships as Disputed or Refuted. The gene-disease relationship curations are publicly available on the ClinGen website (https://clinicalgenome.org/affiliation/40049/). The changes to peroxisomal disease nomenclature are displayed on the Mondo website (http://purl.obolibrary.org/obo/MONDO_0019053). The Peroxisomal GCEP-curated gene-disease relationships will inform clinical and laboratory diagnostics and enhance molecular testing and reporting. As new data will emerge, the gene-disease classifications asserted by the Peroxisomal GCEP will be re-evaluated periodically.

Variant Classification for Pompe disease; ACMG/AMP specifications from the ClinGen Lysosomal Diseases Variant Curation Expert Panel.

Accurate determination of the clinical significance of genetic variants is critical to the integration of genomics in medicine. To facilitate this process, the NIH-funded Clinical Genome Resource (ClinGen) has assembled Variant Curation Expert Panels (VCEPs), groups of experts and biocurators which provide gene- and disease- specifications to the American College of Medical Genetics & Genomics and Association for Molecular Pathology's (ACMG/AMP) variation classification guidelines. With the goal of classifying the clinical significance of GAA variants in Pompe disease (Glycogen storage disease, type II), the ClinGen Lysosomal Diseases (LD) VCEP has specified the ACMG/AMP criteria for GAA. Variant classification can play an important role in confirming the diagnosis of Pompe disease as well as in the identification of carriers. Furthermore, since the inclusion of Pompe disease on the Recommended Uniform Screening Panel (RUSP) for newborns in the USA in 2015, the addition of molecular genetic testing has become an important component in the interpretation of newborn screening results, particularly for asymptomatic individuals. To date, the LD VCEP has submitted classifications and supporting data on 243 GAA variants to public databases, specifically ClinVar and the ClinGen Evidence Repository. Here, we describe the ACMG/AMP criteria specification process for GAA, an update of the GAA-specific variant classification guidelines, and comparison of the ClinGen LD VCEP's GAA variant classifications with variant classifications submitted to ClinVar. The LD VCEP has added to the publicly available knowledge on the pathogenicity of variants in GAA by increasing the number of expert-curated GAA variants present in ClinVar, and aids in resolving conflicting classifications and variants of uncertain clinical significance.

The Gene Curation Coalition: A global effort to harmonize gene-disease evidence resources.

PURPOSE: Several groups and resources provide information that pertains to the validity of gene-disease relationships used in genomic medicine and research; however, universal standards and terminologies to define the evidence base for the role of a gene in disease and a single harmonized resource were lacking. To tackle this issue, the Gene Curation Coalition (GenCC) was formed. METHODS: The GenCC drafted harmonized definitions for differing levels of gene-disease validity on the basis of existing resources, and performed a modified Delphi survey with 3 rounds to narrow the list of terms. The GenCC also developed a unified database to display curated gene-disease validity assertions from its members. RESULTS: On the basis of 241 survey responses from the genetics community, a consensus term set was chosen for grading gene-disease validity and database submissions. As of December 2021, the database contained 15,241 gene-disease assertions on 4569 unique genes from 12 submitters. When comparing submissions to the database from distinct sources, conflicts in assertions of gene-disease validity ranged from 5.3% to 13.4%. CONCLUSION: Terminology standardization, sharing of gene-disease validity classifications, and resolution of curation conflicts will facilitate collaborations across international curation efforts and in turn, improve consistency in genetic testing and variant interpretation.

Discharge Practices for COVID-19 Patients: Rapid Review of Published Guidance and Synthesis of Documents and Practices at 22 US Academic Medical Centers.

BACKGROUND: There are currently no evidence-based guidelines that provide standardized criteria for the discharge of COVID-19 patients from the hospital. OBJECTIVE: To address this gap in practice guidance, we reviewed published guidance and collected discharge protocols and procedures to identify and synthesize common practices. DESIGN: Rapid review of existing guidance from US and non-US public health organizations and professional societies and qualitative review using content analysis of discharge documents collected from a national sample of US academic medical centers with follow-up survey of hospital leaders SETTING AND PARTICIPANTS: We reviewed 65 websites for major professional societies and public health organizations and collected documents from 22 Academic Medical Centers (AMCs) in the US participating in the HOspital MEdicine Reengineering Network (HOMERuN). RESULTS: We synthesized data regarding common practices around 5 major domains: (1) isolation and transmission mitigation; (2) criteria for discharge to non-home settings including skilled nursing, assisted living, or homeless; (3) clinical criteria for discharge including oxygenation levels, fever, and symptom improvement; (4) social support and ability to perform activities of daily living; (5) post-discharge instructions, monitoring, and follow-up. LIMITATIONS: We used streamlined methods for rapid review of published guidance and collected discharge documents only in a focused sample of US academic medical centers. CONCLUSION: AMCs studied showed strong consensus on discharge practices for COVID-19 patients related to post-discharge isolation and transmission mitigation for home and non-home settings. There was high concordance among AMCs that discharge practices should address COVID-19-specific factors in clinical, functional, and post-discharge monitoring domains although definitions and details varied.

Variant interpretation is a component of clinical practice among genetic counselors in multiple specialties.

PURPOSE: Genomic testing is routinely utilized across clinical settings and can have significant variant interpretation challenges. The extent of genetic counselor (GC) engagement in variant interpretation in clinical practice is unknown. This study aimed to explore clinical GCs' variant interpretation practice across specialties, understand outcomes of this practice, and identify resource and educational needs. METHODS: An online survey was administered to National Society of Genetic Counselors members providing clinical counseling. RESULTS: Respondents (n = 239) represented all major clinical specialties. The majority (68%) reported reviewing evidence documented by the laboratory for most (>60%) variants reported; 45.5% report seeking additional evidence. Prenatal GCs were less likely to independently assess reported evidence. Most respondents (67%) report having reached a different conclusion about a variant's classification than the testing laboratory, though infrequently. Time was the most commonly reported barrier (72%) to performing variant interpretation, though the majority (97%) indicated that this practice had an important impact on patient care. When presented with three hypothetical scenarios, evidence typically used for variant interpretation was generally applied correctly. CONCLUSION: This study is the first to document variant interpretation practice broadly across clinical GC specialties. Our results suggest that variant interpretation should be considered a practice-based competency for GCs.

Preoperative evaluation of microvascular invasion with circulating tumour DNA in operable hepatocellular carcinoma.

BACKGROUND & AIMS: Microvascular invasion (MVI) is a critical prognostic factor for operable hepatocellular carcinoma (HCC). This study aimed to explore the performance of circulating tumour DNA (ctDNA) in evaluating MVI status preoperatively. METHODS: Seventy-three HCC patients were enrolled and randomly divided into a training cohort and a validation cohort in a 2:1 ratio, and preoperative blood and surgical tissue samples were obtained. Genomic alterations were analysed using targeted deep sequencing with a 1021-gene panel. RESULTS: In training cohort, 260 somatic mutations were identified in 40 blood samples (81.6%). CtDNA mutation was verified in paired tissue sample in 39 patients (97.5%). In univariate analysis, ctDNA allele frequency (AF) and largest tumour diameter were associated with the presence of MVI, but ctDNA AF was the only independent risk factor in multivariate analysis. With the cut-off value of 0.83%, ctDNA AF determined the presence of MVI with the sensitivity of 89.7% and specificity of 80.0% in the training cohort, and the sensitivity of 78.6% and the specificity of 81.8% in the validation cohort. In preoperative evaluation, ctDNA AF, AFP level and BCLC staging were associated with recurrence-free survival in both univariate and multivariate analysis. CONCLUSIONS: CtDNA can serve as an independent risk factor of MVI for operable HCC and help determining precise treatment strategies. The integration of ctDNA in the management of operable HCC may achieve better clinical outcomes.

Clinical characteristics and genotypes in the ADVANCE baseline data set, a comprehensive cohort of US children and adolescents with Pompe disease.

PURPOSE: To characterize clinical characteristics and genotypes of patients in the ADVANCE study of 4000 L-scale alglucosidase alfa (NCT01526785), the largest prospective United States Pompe disease cohort to date. METHODS: Patients aged ≥1 year with confirmed Pompe disease previously receiving 160 L alglucosidase alfa were eligible. GAA genotypes were determined before/at enrollment. Baseline assessments included histories/physical exams, Gross Motor Function Measure-88 (GMFM-88), pulmonary function tests, and cardiac assessments. RESULTS: Of 113 enrollees (60 male/53 female) aged 1-18 years, 87 had infantile-onset Pompe disease (IOPD) and 26 late-onset (LOPD). One hundred eight enrollees with GAA genotypes had 215 pathogenic variants (220 including combinations): 118 missense (4 combinations), 23 splice, 35 nonsense, 34 insertions/deletions, 9 duplications (1 combination), 6 other; c.2560C>T (n = 23), c.-32-13T>G (n = 13), and c.525delT (n = 12) were most common. Four patients had previously unpublished variants, and 14/83 (17%) genotyped IOPD patients were cross-reactive immunological material-negative. All IOPD and 6/26 LOPD patients had cardiac involvement, all without c.-32-13T>G. Thirty-two (26 IOPD, 6 LOPD) were invasively ventilated. GMFM-88 total %scores (mean ± SD, median, range): overall 46.3 ± 33.0% (47.9%, 0.0-100.0%), IOPD 41.6 ± 31.64% (38.9%, 0.0-99.7%), LOPD: 61.8 ± 33.2 (70.9%, 0.0-100.0%). CONCLUSION: ADVANCE, a uniformly assessed cohort comprising most US children and adolescents with treated Pompe disease, expands understanding of the phenotype and observed variants in the United States.

Diagnosis and management of glycogen storage diseases type VI and IX: a clinical practice resource of the American College of Medical Genetics and Genomics (ACMG).

PURPOSE: Glycogen storage disease (GSD) types VI and IX are rare diseases of variable clinical severity affecting primarily the liver. GSD VI is caused by deficient activity of hepatic glycogen phosphorylase, an enzyme encoded by the PYGL gene. GSD IX is caused by deficient activity of phosphorylase kinase (PhK), the enzyme subunits of which are encoded by various genes: ɑ (PHKA1, PHKA2), ß (PHKB), É£ (PHKG1, PHKG2), and δ (CALM1, CALM2, CALM3). Glycogen storage disease types VI and IX have a wide spectrum of clinical manifestations and often cannot be distinguished from each other, or from other liver GSDs, on clinical presentation alone. Individuals with GSDs VI and IX can present with hepatomegaly with elevated serum transaminases, ketotic hypoglycemia, hyperlipidemia, and poor growth. This guideline for the management of GSDs VI and IX was developed as an educational resource for health-care providers to facilitate prompt and accurate diagnosis and appropriate management of patients. METHODS: A national group of experts in various aspects of GSDs VI and IX met to review the limited evidence base from the scientific literature and provided their expert opinions. Consensus was developed in each area of diagnosis, treatment, and management. Evidence bases for these rare disorders are largely based on expert opinion, particularly when targeted therapeutics that have to clear the US Food and Drug Administration (FDA) remain unavailable. RESULTS: This management guideline specifically addresses evaluation and diagnosis across multiple organ systems involved in GSDs VI and IX. Conditions to consider in a differential diagnosis stemming from presenting features and diagnostic algorithms are discussed. Aspects of diagnostic evaluation and nutritional and medical management, including care coordination, genetic counseling, and prenatal diagnosis are addressed. CONCLUSION: A guideline that will facilitate the accurate diagnosis and optimal management of patients with GSDs VI and IX was developed. This guideline will help health-care providers recognize patients with GSDs VI and IX, expedite diagnosis, and minimize adverse sequelae from delayed diagnosis and inappropriate management. It will also help identify gaps in scientific knowledge that exist today and suggest future studies.

"Implications of cost-sharing for observation care among Medicare beneficiaries: a pilot survey".

BACKGROUND: Medicare beneficiaries hospitalized under observation status have significant cost-sharing responsibilities under Medicare Part B. Prior work has demonstrated an association between increased cost-sharing and health care rationing among low-income Medicare beneficiaries. The objective of this study was to explore the potential impact of observation cost-sharing on future medical decision making of Medicare beneficiaries. METHODS: Single-center pilot cohort study. A convenience sample of Medicare beneficiaries hospitalized under observation status care was surveyed. RESULTS: Out of 144 respondents, low-income beneficiaries were more likely to be concerned about the cost of their observation stay than higher-income respondents (70.7% vs29.3%, p = 0.015). If hospitalized under observation status again, there was a trend among low-income beneficiaries to request completion of their workup outside of the hospital (56.3% vs 43.8%), and to consider leaving against medical advice (AMA) (100% vs 0%), though these trends were not statistically significant (p = 0.30). CONCLUSION: The results of this pilot study suggest that low-income Medicare beneficiaries hospitalized under observation status have greater concerns about their cost-sharing obligations than their higher income peers. Cost-sharing for observation care may have unintended consequences on utilization for low-income beneficiaries. Future studies should examine this potential relationship on a larger scale.

The progression of the ClinGen gene clinical validity classification over time.

In order for ClinGen to maintain up-to-date gene-disease clinical validity classifications for use by clinicians and clinical laboratories, an appropriate timeline for reevaluating curated gene-disease associations will need to be determined. To provide guidance on how often a gene-disease association should be recurated, a retrospective analysis of 30 gene curations was performed. Curations were simulated at one-year intervals starting with the year of the first publication to assert disease-causing variants in the gene to observe trends in the classification over time, as well as factors that influenced changes in classification. On average, gene-disease associations spent the least amount of time in the "Moderate" classification before progressing to "Strong" or "Definitive." In contrast, gene-disease associations that spent five or more years in the "Limited" classification were most likely to remain "Limited" or become "Disputed/Refuted." Large population datasets contributed to the reclassification of several gene-disease associations from "Limited" to "Disputed/Refuted." Finally, recent advancements in sequencing technology correlated with an increase in the quantity of case-level evidence that was curated per paper. This study provided a number of key points to consider when determining how often to recurate a gene-disease association.

Treatment outcome of creatine transporter deficiency: international retrospective cohort study.

To evaluate the outcome of current treatment for creatine transporter (CRTR) deficiency, we developed a clinical severity score and initiated an international treatment registry. An online questionnaire was completed by physicians following patients with CRTR deficiency on a treatment, including creatine and/or arginine, and/or glycine. Clinical severity score included 1) global developmental delay/intellectual disability; 2) seizures; 3) behavioural disorder. Phenotype scored 1-3 = mild; 4-6 = moderate; and 7-9 = severe. We applied the clinical severity score pre- and on-treatment. Seventeen patients, 14 males and 3 females, from 16 families were included. Four patients had severe, 6 patients had moderate, and 7 patients had a mild phenotype. The phenotype ranged from mild to severe in patients diagnosed at or before 2 years of age or older than 6 years of age. The phenotype ranged from mild to severe in patients with mildly elevated urine creatine to creatinine ratio. Fourteen patients were on the combined creatine, arginine and glycine therapy. On the combined treatment with creatine, arginine and glycine, none of the males showed either deterioration or improvements in their clinical severity score, whereas two females showed improvements in the clinical severity score. Creatine monotherapy resulted in deterioration of the clinical severity score in one male. There seems to be no correlation between phenotype and degree of elevation in urine creatine to creatinine ratio, genotype, or age at diagnosis. Combined creatine, arginine and glycine therapy might have stopped disease progression in males and improved phenotype in females.

Sensitivity of whole exome sequencing in detecting infantile- and late-onset Pompe disease.

Pompe disease is a metabolic myopathy with a wide spectrum of clinical presentation. The gold-standard diagnostic test is acid alpha-glucosidase assay on skin fibroblasts, muscle or blood. Identification of two GAA pathogenic variants in-trans is confirmatory. Optimal effectiveness of enzyme replacement therapy hinges on early diagnosis, which is challenging in late-onset form of the disease due to non-specific presentation. Next-generation sequencing-based panels effectively facilitate diagnosis, but the sensitivity of whole-exome sequencing (WES) in detecting pathogenic GAA variants remains unknown. We analyzed WES data from 93 patients with confirmed Pompe disease and GAA genotypes based on PCR/Sanger sequencing. After ensuring that the common intronic variant c.-32-13T>G is not filtered out, whole-exome sequencing identified both GAA pathogenic variants in 77/93 (83%) patients. However, one variant was missed in 14/93 (15%), and both variants were missed in 2/93 (2%). One complex indel leading to a severe phenotype was incorrectly called a nonsynonymous substitution c.-32-13T>C due to misalignment. These results demonstrate that WES may fail to diagnose Pompe disease. Clinicians need to be aware of limitations of WES, and consider tests specific to Pompe disease when WES does not provide a diagnosis in patients with proximal myopathy, progressive respiratory failure or other subtle symptoms.

Epigenetic dysregulation of SHANK3 in brain tissues from individuals with autism spectrum disorders.

The molecular basis for the majority of cases of autism spectrum disorders (ASD) remains unknown. We tested the hypothesis that ASD have an epigenetic cause by performing DNA methylation profiling of five CpG islands (CGI-1 to CGI-5) in the SHANK3 gene in postmortem brain tissues from 54 ASD patients and 43 controls. We found significantly increased overall DNA methylation (epimutation) in three intragenic CGIs (CGI-2, CGI-3 and CGI-4). The increased methylation was clustered in the CGI-2 and CGI-4 in ∼15% of ASD brain tissues. SHANK3 has an extensive array of mRNA splice variants resulting from combinations of five intragenic promoters and alternative splicing of coding exons. Altered expression and alternative splicing of SHANK3 isoforms were observed in brain tissues with increased methylation of SHANK3 CGIs in ASD brain tissues. A DNA methylation inhibitor modified the methylation of CGIs and altered the isoform-specific expression of SHANK3 in cultured cells. This study is the first to find altered methylation patterns in SHANK3 in ASD brain samples. Our finding provides evidence to support an alternative approach to investigating the molecular basis of ASD. The ability to alter the epigenetic modification and expression of SHANK3 by environmental factors suggests that SHANK3 may be a valuable biomarker for dissecting the role of gene and environment interaction in the etiology of ASD.

New observation of sialuria prompts detection of liver tumor in previously reported patient.

UNLABELLED: Sialuria, a rare inborn error of metabolism, was diagnosed in a healthy 12-year-old boy through whole exome sequencing. The patient had experienced mild delays of speech and motor development, as well as persistent hepatomegaly. Identification of the 8th individual with this disorder, prompted follow-up of the mother-son pair of patients diagnosed over 15years ago. Hepatomegaly was confirmed in the now 19-year-old son, but in the 46-year-old mother a clinically silent liver tumor was detected by ultrasound and MRI. The tumor was characterized as an intrahepatic cholangiocarcinoma (IHCC) and DNA analysis of both tumor and normal liver tissue confirmed the original GNE mutation. As the maternal grandmother in the latter family died at age 49years of a liver tumor, a retrospective study of the remaining pathology slides was conducted and confirmed it to have been an IHCC as well. The overall observation generated the hypothesis that sialuria may predispose to development of this form of liver cancer. As proof of sialuria in the grandmother could not be obtained, an alternate cause of IHCC cannot be ruled out. In a series of 102 patients with IHCC, not a single instance was found with the allosteric site mutation in the GNE gene. This confirms that sialuria is rare even in a selected group of patients, but does not invalidate the concern that sialuria may be a risk factor for IHCC. SYNOPSIS: Sialuria is a rare inborn error of metabolism characterized by excessive synthesis and urinary excretion of free sialic acid with only minimal clinical morbidity in early childhood, but may be a risk factor for intrahepatic cholangiocarcinoma in adulthood.

Is the Care Transitions Measure Associated with Readmission Risk? Analysis from a Single Academic Center.

BACKGROUND: It is widely hypothesized that improvement in transitions of care will reduce unplanned hospital readmissions. However, the association between the Care Transitions Measure, the national quality metric for transitions of care and readmission risk, has not been established. OBJECTIVE: We aimed to determine the association between the Care Transition Measure and readmission. DESIGN: This was a single-center, prospective cohort study. PARTICIPANTS: Convenience sample of 2,963 patients enrolled in the "Bridging the Divides" program, a longitudinal care management program for patients with coronary revascularization, from 2013 to 2014. Of these, 1594 (54 %) patients completed a post-discharge Care Transition Measure questionnaire. INTERVENTION: Care Transition Measure scores were collected by trained research staff blinded to study hypothesis, by telephone, within 30 days of discharge. Higher Care Transition Measure scores reflect a higher quality transition of care. MAIN MEASURES: 30-day readmission was measured. KEY RESULTS: Of the1594 patients that completed the Care Transition Measure survey, 1216 (76 %) received percutaneous coronary intervention and 378 (24 %) received coronary artery bypass grafting. Mean Care Transition Measure scores were significantly lower among patients who had a prior admission (77.2 vs. 82.1, p < 0.001) and those with ≥ 5 comorbidities (77 vs. 82.6 vs. 81.6, p < 0.001). Mean scores were significantly lower among patients who were readmitted within the percutaneous coronary intervention subgroup (73 vs. 80.9, p < 0.001) and the total study population (74.6 vs. 81.1, p < 0.001) compared to those who were not readmitted. This was not the case in the coronary artery bypass grafting subgroup (78.5 vs. 81.7, p = 0.29). After multivariable adjustment, every ten-point increase in the Care Transition Measure score was associated with a 14 % reduction in readmission risk (adjusted odds ratio 0.86, 95 % CI 0.78-0.95). CONCLUSIONS: The Care Transition Measure is strongly associated with readmissions, which strengthens its validity. However, its association with patient variables linked with readmission and its inconsistent association with readmission across clinical groups raises concerns that scores may be influenced by patient characteristics.

Chromosomal microarray analysis in clinical evaluation of neurodevelopmental disorders-reporting a novel deletion of SETDB1 and illustration of counseling challenge.

BACKGROUND: The pathogenicity of copy number variations (CNV) in neurodevelopmental disorders is supported by research literature. However, few studies have evaluated the utility and counseling challenges of CNV analysis in clinic. METHODS: We analyzed the findings of CNV studies from a cohort referred for genetics evaluation of autism spectrum disorders (ASD), developmental disability (DD), and intellectual disability (ID). RESULTS: Twenty-two CNV in 21 out of 115 probands are considered to be pathogenic (18.3%). Five CNV are likely pathogenic and 22 CNV are variants of unknown significance (VUS). We have found seven cases with more than two CNV and two with a complex rearrangement of the 22q13.3 Phelan-McDermid syndrome region. We identified a new and de novo 1q21.3 deletion that encompasses SETDB1, a gene encoding methylates histone H3 on lysine-9 (H3K9) methyltransferase, in a case with ASD. CONCLUSION: We provide evidence to support the value of CNV analysis in etiological evaluation of neurodevelopmental disorders in autism genetics clinic. However, interpretation of the clinical significance and counseling families are still challenging because of the variable penetrance and pleotropic expressivity of CNV. In addition, the identification of a 1q21.3 deletion encompassing SETDB1 provides further support for the role of chromatin modifiers in the etiology of ASD.

Cutaneous Metastasis of a Mucoepidermoid Carcinoma of the Pancreas: First Reported Case.

BACKGROUND: Mucoepidermoid pancreatic cancer is a rare entity with only 8 cases reported in the literature. On review of the literature, the authors found that cutaneous metastases in pancreatic cancer are rare and have not been associated with the mucoepidermoid subtype. The authors present the first reported case of cutaneous metastasis in a patient with mucoepidermoid carcinoma of the pancreas. CASE PRESENTATION: A 50-year old white male with a metastatic invasive poorly differentiated mucoepidermoid carcinoma of the pancreas was found to have a slow growing lesion in the skin over his left upper quadrant while undergoing active therapy. The lesion was biopsied and the pathology was consistent with pancreatic origin sharing similar morphologic features when compared with the primary pancreactectomy specimen. CONCLUSIONS: Mucoepidermoid pancreatic cancer is an exceedingly rare subtype of pancreatic cancer, with very little information regarding its diagnosis, treatment, and patterns of metastases. Here, the authors present the first reported case of cutaneous metastases of mucoepidermoid pancreatic cancer.

CRIM-negative infantile Pompe disease: characterization of immune responses in patients treated with ERT monotherapy.

PURPOSE: Enzyme replacement therapy (ERT) with recombinant human acid α-glucosidase (rhGAA) prolongs survival in infantile Pompe disease (IPD). However, the majority of cross-reactive immunologic material (CRIM)-negative (CN) patients have immune responses with significant clinical decline despite continued ERT. We aimed to characterize immune responses in CN patients with IPD receiving ERT monotherapy. METHODS: A chart review identified 20 CN patients with IPD treated with ERT monotherapy for ≥6 months. Patients were stratified by anti-rhGAA antibody titers: high sustained antibody titers (HSAT; ≥51,200) at least twice; low titers (LT; <6,400) throughout treatment; or sustained intermediate titers (SIT; 6,400-25,600). RESULTS: Despite early initiation of treatment, the majority (85%) of CN patients developed significant antibody titers, most with HSAT associated with invasive ventilation and death. Nearly all patients with HSAT had at least one nonsense GAA mutation, whereas the LT group exclusively carried splice-site or frameshift mutations. Only one patient in the HSAT group is currently alive after successful immune modulation in the entrenched setting. CONCLUSION: Immunological responses are a significant risk in CN IPD; thus induction of immune tolerance in the naive setting should strongly be considered. Further exploration of factors influencing immune responses is required, particularly with the advent of newborn screening for Pompe disease.