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Witteveen–Kolk syndrome (WITKOS) is a rare neurodevelopmental disorder characterized by developmental delay/intellectual disability, facial dysmorphisms, and short stature. The syndrome is caused by loss of function of switch‐insensitive 3 transcription regulator family member A (SIN3A). Regarding behavioral functioning, Autism Spectrum Disorders (ASD), obsessive–compulsive behaviors, as well as Attention‐Deficit/Hyperactivity Disorder symptoms (ADHD) have been suggested. The present study explores various aspects of neurocognitive functioning in five individuals (age range 10–23) with WITKOS. Medical records and results of extensive neuropsychological assessment are used to describe developmental trajectories and neurocognitive profiles. Systematic analysis of medical records displays developmental difficulties described as ASD or ADHD in childhood, sleep problems and internalizing problems during adolescence. Results of cognitive assessments indicate profoundly disabled (n = 1), mildly disabled (n = 2), borderline (n = 1), and average (n = 1) levels of intelligence. Furthermore, results indicate weaknesses in speed of information processing/sustained attention in all participants, and difficulties in planning and maintaining overview in three participants. Furthermore, parent reports of behavioral functioning primarily suggest problems in social functioning. Implications of both cognitive problems and social–emotional vulnerabilities for counseling are discussed and supplemented with suggestions for interventions. [ABSTRACT FROM AUTHOR]

Background: ARID1A/ARID1B haploinsufficiency leads to Coffin-Siris syndrome, duplications of ARID1A lead to a distinct clinical syndrome, whilst ARID1B duplications have not yet been linked to a phenotype., Methods: We collected patients with duplications encompassing ARID1A and ARID1B duplications., Results: 16 ARID1A and 13 ARID1B duplication cases were included with duplication sizes ranging from 0.1-1.2 Mb(1-44 genes) for ARID1A and 0.9-10.3 Mb(2-101 genes) for ARID1B. Both groups shared features, with ARID1A patients having more severe intellectual disability, growth delay and congenital anomalies. DNA methylation analysis showed that ARID1A patients had a specific methylation pattern in blood, which differed from controls and from patients with ARID1A or ARID1B loss-of-function variants. ARID1B patients appeared to have a distinct methylation pattern, similar to ARID1A duplication patients, but further research is needed to validate these results. Five cases with duplications including ARID1A or ARID1B initially annotated as duplications of uncertain significance were evaluated using PhenoScore and DNA methylation re-analysis, resulting in the reclassification of two ARID1A and two ARID1B duplications as pathogenic., Conclusion: Our findings reveal that ARID1B duplications manifest a clinical phenotype and ARID1A duplications have a distinct episignature that overlaps with that of ARID1B duplications, providing further evidence for a distinct and emerging BAFopathy caused by whole gene duplication rather than haploinsufficiency., (Copyright © 2024. Published by Elsevier Inc.)

The shift to a genotype-first approach in genetic diagnostics has revolutionized our understanding of neurodevelopmental disorders, expanding both their molecular and phenotypic spectra. Kleefstra syndrome (KLEFS1) is caused by EHMT1 haploinsufficiency and exhibits broad clinical manifestations. EHMT1 encodes euchromatic histone methyltransferase-1-a pivotal component of the epigenetic machinery. We have recruited 209 individuals with a rare EHMT1 variant and performed comprehensive molecular in silico and in vitro testing alongside DNA methylation (DNAm) signature analysis for the identified variants. We (re)classified the variants as likely pathogenic/pathogenic (molecularly confirming Kleefstra syndrome) in 191 individuals. We provide an updated and broader clinical and molecular spectrum of Kleefstra syndrome, including individuals with normal intelligence and familial occurrence. Analysis of the EHMT1 variants reveals a broad range of molecular effects and their associated phenotypes, including distinct genotype-phenotype associations. Notably, we showed that disruption of the "reader" function of the ankyrin repeat domain by a protein altering variant (PAV) results in a KLEFS1-specific DNAm signature and milder phenotype, while disruption of only "writer" methyltransferase activity of the SET domain does not result in KLEFS1 DNAm signature or typical KLEFS1 phenotype. Similarly, N-terminal truncating variants result in a mild phenotype without the DNAm signature. We demonstrate how comprehensive variant analysis can provide insights into pathogenesis of the disorder and DNAm signature. In summary, this study presents a comprehensive overview of KLEFS1 and EHMT1, revealing its broader spectrum and deepening our understanding of its molecular mechanisms, thereby informing accurate variant interpretation, counseling, and clinical management., Competing Interests: Declaration of interests A.M.M. is an employee of GeneDx, LLC. B.S. is a shareholder in EpiSign Inc., a biotechnology company involved in commercialization of EpiSign technology., (Copyright © 2024 American Society of Human Genetics. All rights reserved.)

Trithorax-related H3K4 methyltransferases, KMT2C and KMT2D, are critical epigenetic modifiers. Haploinsufficiency of KMT2C was only recently recognized as a cause of neurodevelopmental disorder (NDD), so the clinical and molecular spectrums of the KMT2C-related NDD (now designated as Kleefstra syndrome 2) are largely unknown. We ascertained 98 individuals with rare KMT2C variants, including 75 with protein-truncating variants (PTVs). Notably, ∼15% of KMT2C PTVs were inherited. Although the most highly expressed KMT2C transcript consists of only the last four exons, pathogenic PTVs were found in almost all the exons of this large gene. KMT2C variant interpretation can be challenging due to segmental duplications and clonal hematopoesis-induced artifacts. Using samples from 27 affected individuals, divided into discovery and validation cohorts, we generated a moderate strength disorder-specific KMT2C DNA methylation (DNAm) signature and demonstrate its utility in classifying non-truncating variants. Based on 81 individuals with pathogenic/likely pathogenic variants, we demonstrate that the KMT2C-related NDD is characterized by developmental delay, intellectual disability, behavioral and psychiatric problems, hypotonia, seizures, short stature, and other comorbidities. The facial module of PhenoScore, applied to photographs of 34 affected individuals, reveals that the KMT2C-related facial gestalt is significantly different from the general NDD population. Finally, using PhenoScore and DNAm signatures, we demonstrate that the KMT2C-related NDD is clinically and epigenetically distinct from Kleefstra and Kabuki syndromes. Overall, we define the clinical features, molecular spectrum, and DNAm signature of the KMT2C-related NDD and demonstrate they are distinct from Kleefstra and Kabuki syndromes highlighting the need to rename this condition., Competing Interests: Declaration of interests R.W. is a consultant (equity) for Alamya Health., (Copyright © 2024 American Society of Human Genetics. All rights reserved.)

Mutations in ADNP result in Helsmoortel-Van der Aa syndrome. Here, we describe the first de novo intronic deletion, affecting the splice-acceptor site of the first coding ADNP exon in a five-year-old girl with developmental delay and autism. Whereas exome sequencing failed to detect the non-coding deletion, genome-wide CpG methylation analysis revealed an episignature suggestive of a Helsmoortel-Van der Aa syndrome diagnosis. This diagnosis was further supported by PhenoScore, a novel facial recognition software package. Subsequent whole-genome sequencing resolved the three-base pair ADNP deletion c.[-5-1_-4del] with transcriptome sequencing showing this deletion leads to skipping of exon 4. An N-terminal truncated protein could not be detected in transfection experiments with a mutant expression vector in HEK293T cells, strongly suggesting this is a first confirmed diagnosis exclusively due to haploinsufficiency of the ADNP gene. Pathway analysis of the methylome indicated differentially methylated genes involved in brain development, the cytoskeleton, locomotion, behavior, and muscle development. Along the same line, transcriptome analysis identified most of the differentially expressed genes as upregulated, in line with the hypomethylated CpG episignature and confirmed the involvement of the cytoskeleton and muscle development pathways that are also affected in patient cell lines and animal models. In conclusion, this novel mutation for the first time demonstrates that Helsmoortel-Van der Aa syndrome can be caused by a loss-of-function mutation. Moreover, our study elegantly illustrates the use of EpiSignatures, WGS and Phenoscore as novel complementary diagnostic tools in case a of negative WES result., (© 2024. The Author(s), under exclusive licence to European Society of Human Genetics.)

Pathogenic variants in KANSL1 and 17q21.31 microdeletions are causative of Koolen-de Vries syndrome (KdVS), a neurodevelopmental syndrome with characteristic facial dysmorphia. Our previous work has shown that syndromic conditions caused by pathogenic variants in epigenetic regulatory genes have identifiable patterns of DNA methylation (DNAm) change: DNAm signatures or episignatures. Given the role of KANSL1 in histone acetylation, we tested whether variants underlying KdVS are associated with a DNAm signature. We profiled whole-blood DNAm for 13 individuals with KANSL1 variants, four individuals with 17q21.31 microdeletions, and 21 typically developing individuals, using Illumina's Infinium EPIC array. In this study, we identified a robust DNAm signature of 456 significant CpG sites in 8 individuals with KdVS, a pattern independently validated in an additional 7 individuals with KdVS. We also demonstrate the diagnostic utility of the signature and classify two KANSL1 VUS as well as four variants in individuals with atypical clinical presentation. Lastly, we investigated tissue-specific DNAm changes in fibroblast cells from individuals with KdVS. Collectively, our findings contribute to the understanding of the epigenetic landscape related to KdVS and aid in the diagnosis and classification of variants in this structurally complex genomic region., (© 2024. The Author(s).)

Purpose: Hao-Fountain syndrome (HAFOUS) is a neurodevelopmental disorder caused by pathogenic variants in USP7. HAFOUS is characterized by developmental delay, intellectual disability, speech delay, behavioral abnormalities, autism spectrum disorder, seizures, hypogonadism, and mild dysmorphic features. We investigated the phenotype of 18 participants with HAFOUS and performed DNA methylation (DNAm) analysis, aiming to generate a diagnostic biomarker. Furthermore, we performed comparative analysis with known episignatures to gain more insight into the molecular pathophysiology of HAFOUS., Methods: We assessed genomic DNAm profiles of 18 individuals with pathogenic variants and variants of uncertain significance (VUS) in USP7 to map and validate a specific episignature. The comparison between the USP7 cohort and 56 rare genetic disorders with earlier reported DNAm episignatures was performed with statistical and functional correlation., Results: We mapped a sensitive and specific DNAm episignature for pathogenic variants in USP7 and utilized this to reclassify the VUS. Comparative epigenomic analysis showed evidence of HAFOUS similarity to a number of other rare genetic episignature disorders., Conclusion: We discovered a sensitive and specific DNAm episignature as a robust diagnostic biomarker for HAFOUS that enables VUS reclassification in USP7. We also expand the phenotypic spectrum of 9 new and 5 previously reported individuals with HAFOUS., Competing Interests: Conflict of Interest Bekim Sadikovic is a shareholder in EpiSign Inc., a biotech firm involved in commercial application of EpiSign technology. All other authors declare no conflicts of interest., (Copyright © 2023 The Authors. Published by Elsevier Inc. All rights reserved.)

The Human Phenotype Ontology (HPO) is a widely used resource that comprehensively organizes and defines the phenotypic features of human disease, enabling computational inference and supporting genomic and phenotypic analyses through semantic similarity and machine learning algorithms. The HPO has widespread applications in clinical diagnostics and translational research, including genomic diagnostics, gene-disease discovery, and cohort analytics. In recent years, groups around the world have developed translations of the HPO from English to other languages, and the HPO browser has been internationalized, allowing users to view HPO term labels and in many cases synonyms and definitions in ten languages in addition to English. Since our last report, a total of 2239 new HPO terms and 49235 new HPO annotations were developed, many in collaboration with external groups in the fields of psychiatry, arthrogryposis, immunology and cardiology. The Medical Action Ontology (MAxO) is a new effort to model treatments and other measures taken for clinical management. Finally, the HPO consortium is contributing to efforts to integrate the HPO and the GA4GH Phenopacket Schema into electronic health records (EHRs) with the goal of more standardized and computable integration of rare disease data in EHRs., (© The Author(s) 2023. Published by Oxford University Press on behalf of Nucleic Acids Research.)

Purpose: Witteveen-Kolk syndrome (WITKOS) is a rare, autosomal dominant neurodevelopmental disorder caused by heterozygous loss-of-function alterations in the SIN3A gene. WITKOS has variable expressivity that commonly overlaps with other neurodevelopmental disorders. In this study, we characterized a distinct DNA methylation epigenetic signature (episignature) distinguishing WITKOS from unaffected individuals as well as individuals with other neurodevelopmental disorders with episignatures and described 9 previously unpublished individuals with SIN3A haploinsufficiency., Methods: We studied the phenotypic characteristics and the genome-wide DNA methylation in the peripheral blood samples of 20 individuals with heterozygous alterations in SIN3A. A total of 14 samples were used for the identification of the episignature and building of a predictive diagnostic biomarker, whereas the diagnostic model was used to investigate the methylation pattern of the remaining 6 samples., Results: A predominantly hypomethylated DNA methylation profile specific to WITKOS was identified, and the classifier model was able to diagnose a previously unresolved test case. The episignature was sensitive enough to detect individuals with varying degrees of phenotypic severity carrying SIN3A haploinsufficient variants., Conclusion: We identified a novel, robust episignature in WITKOS due to SIN3A haploinsufficiency. This episignature has the potential to aid identification and diagnosis of individuals with WITKOS., Competing Interests: Conflict of Interest The authors declare no conflicts of interest., (Copyright © 2022 American College of Medical Genetics and Genomics. Published by Elsevier Inc. All rights reserved.)

Purpose: Although haploinsufficiency of ANKRD11 is among the most common genetic causes of neurodevelopmental disorders, the role of rare ANKRD11 missense variation remains unclear. We characterized clinical, molecular, and functional spectra of ANKRD11 missense variants., Methods: We collected clinical information of individuals with ANKRD11 missense variants and evaluated phenotypic fit to KBG syndrome. We assessed pathogenicity of variants through in silico analyses and cell-based experiments., Results: We identified 20 unique, mostly de novo, ANKRD11 missense variants in 29 individuals, presenting with syndromic neurodevelopmental disorders similar to KBG syndrome caused by ANKRD11 protein truncating variants or 16q24.3 microdeletions. Missense variants significantly clustered in repression domain 2 at the ANKRD11 C-terminus. Of the 10 functionally studied missense variants, 6 reduced ANKRD11 stability. One variant caused decreased proteasome degradation and loss of ANKRD11 transcriptional activity., Conclusion: Our study indicates that pathogenic heterozygous ANKRD11 missense variants cause the clinically recognizable KBG syndrome. Disrupted transrepression capacity and reduced protein stability each independently lead to ANKRD11 loss-of-function, consistent with haploinsufficiency. This highlights the diagnostic relevance of ANKRD11 missense variants, but also poses diagnostic challenges because the KBG-associated phenotype may be mild and inherited pathogenic ANKRD11 (missense) variants are increasingly observed, warranting stringent variant classification and careful phenotyping., Competing Interests: Conflict of Interest H.Z.E. and K.G.M. are employees of GeneDx, Inc. All other authors declare no conflicts of interest., (Copyright © 2022 The Authors. Published by Elsevier Inc. All rights reserved.)

Purpose: Common diagnostic next-generation sequencing strategies are not optimized to identify inherited variants in genes associated with dominant neurodevelopmental disorders as causal when the transmitting parent is clinically unaffected, leaving a significant number of cases with neurodevelopmental disorders undiagnosed., Methods: We characterized 21 families with inherited heterozygous missense or protein-truncating variants in CHD3, a gene in which de novo variants cause Snijders Blok-Campeau syndrome., Results: Computational facial and Human Phenotype Ontology-based comparisons showed that the phenotype of probands with inherited CHD3 variants overlaps with the phenotype previously associated with de novo CHD3 variants, whereas heterozygote parents are mildly or not affected, suggesting variable expressivity. In addition, similarly reduced expression levels of CHD3 protein in cells of an affected proband and of healthy family members with a CHD3 protein-truncating variant suggested that compensation of expression from the wild-type allele is unlikely to be an underlying mechanism. Notably, most inherited CHD3 variants were maternally transmitted., Conclusion: Our results point to a significant role of inherited variation in Snijders Blok-Campeau syndrome, a finding that is critical for correct variant interpretation and genetic counseling and warrants further investigation toward understanding the broader contributions of such variation to the landscape of human disease., Competing Interests: Conflict of Interest M.L.T. is an employee of HudsonAlpha Institute for Biotechnology. For D.M., the following statements are applicable: “Research disclaimer: The views expressed in this article reflect the results of research conducted by the authors and do not necessarily reflect the official policy or position of the Department of the Navy, Department of Defense, or the United States Government. Copyright statement: I am a military service member. This work was prepared as part of my official duties. Title 17 U.S.C. 105 provides that "Copyright protection under this title is not available for any work of the United States Government." Title 17 U.S.C. 101 defines a United States Government work as a work prepared by a military service member or employee of the United States Government as part of that person’s official duties.” All other authors declare no conflicts of interest., (Copyright © 2022 American College of Medical Genetics and Genomics. All rights reserved.)

Purpose: Although the introduction of exome sequencing (ES) has led to the diagnosis of a significant portion of patients with neurodevelopmental disorders (NDDs), the diagnostic yield in actual clinical practice has remained stable at approximately 30%. We hypothesized that improving the selection of patients to test on the basis of their phenotypic presentation will increase diagnostic yield and therefore reduce unnecessary genetic testing., Methods: We tested 4 machine learning methods and developed PredWES from these: a statistical model predicting the probability of a positive ES result solely on the basis of the phenotype of the patient., Results: We first trained the tool on 1663 patients with NDDs and subsequently showed that diagnostic ES on the top 10% of patients with the highest probability of a positive ES result would provide a diagnostic yield of 56%, leading to a notable 114% increase. Inspection of our model revealed that for patients with NDDs, comorbid abnormal (lower) muscle tone and microcephaly positively correlated with a conclusive ES diagnosis, whereas autism was negatively associated with a molecular diagnosis., Conclusion: In conclusion, PredWES allows prioritizing patients with NDDs eligible for diagnostic ES on the basis of their phenotypic presentation to increase the diagnostic yield, making a more efficient use of health care resources., Competing Interests: Conflict of Interest The authors declare no conflicts of interests., (Copyright © 2021. Published by Elsevier Inc.)

Truncating variants in exons 33 and 34 of the SNF2-related CREBBP activator protein (SRCAP) gene cause the neurodevelopmental disorder (NDD) Floating-Harbor syndrome (FLHS), characterized by short stature, speech delay, and facial dysmorphism. Here, we present a cohort of 33 individuals with clinical features distinct from FLHS and truncating (mostly de novo) SRCAP variants either proximal (n = 28) or distal (n = 5) to the FLHS locus. Detailed clinical characterization of the proximal SRCAP individuals identified shared characteristics: developmental delay with or without intellectual disability, behavioral and psychiatric problems, non-specific facial features, musculoskeletal issues, and hypotonia. Because FLHS is known to be associated with a unique set of DNA methylation (DNAm) changes in blood, a DNAm signature, we investigated whether there was a distinct signature associated with our affected individuals. A machine-learning model, based on the FLHS DNAm signature, negatively classified all our tested subjects. Comparing proximal variants with typically developing controls, we identified a DNAm signature distinct from the FLHS signature. Based on the DNAm and clinical data, we refer to the condition as "non-FLHS SRCAP-related NDD." All five distal variants classified negatively using the FLHS DNAm model while two classified positively using the proximal model. This suggests divergent pathogenicity of these variants, though clinically the distal group presented with NDD, similar to the proximal SRCAP group. In summary, for SRCAP, there is a clear relationship between variant location, DNAm profile, and clinical phenotype. These results highlight the power of combined epigenetic, molecular, and clinical studies to identify and characterize genotype-epigenotype-phenotype correlations., (Copyright © 2021 The Author(s). Published by Elsevier Inc. All rights reserved.)

Whereas large-scale statistical analyses can robustly identify disease-gene relationships, they do not accurately capture genotype-phenotype correlations or disease mechanisms. We use multiple lines of independent evidence to show that different variant types in a single gene, SATB1, cause clinically overlapping but distinct neurodevelopmental disorders. Clinical evaluation of 42 individuals carrying SATB1 variants identified overt genotype-phenotype relationships, associated with different pathophysiological mechanisms, established by functional assays. Missense variants in the CUT1 and CUT2 DNA-binding domains result in stronger chromatin binding, increased transcriptional repression, and a severe phenotype. In contrast, variants predicted to result in haploinsufficiency are associated with a milder clinical presentation. A similarly mild phenotype is observed for individuals with premature protein truncating variants that escape nonsense-mediated decay, which are transcriptionally active but mislocalized in the cell. Our results suggest that in-depth mutation-specific genotype-phenotype studies are essential to capture full disease complexity and to explain phenotypic variability., (Copyright © 2021 American Society of Human Genetics. Published by Elsevier Inc. All rights reserved.)

The Rho-guanine nucleotide exchange factor (RhoGEF) TRIO acts as a key regulator of neuronal migration, axonal outgrowth, axon guidance, and synaptogenesis by activating the GTPase RAC1 and modulating actin cytoskeleton remodeling. Pathogenic variants in TRIO are associated with neurodevelopmental diseases, including intellectual disability (ID) and autism spectrum disorders (ASD). Here, we report the largest international cohort of 24 individuals with confirmed pathogenic missense or nonsense variants in TRIO. The nonsense mutations are spread along the TRIO sequence, and affected individuals show variable neurodevelopmental phenotypes. In contrast, missense variants cluster into two mutational hotspots in the TRIO sequence, one in the seventh spectrin repeat and one in the RAC1-activating GEFD1. Although all individuals in this cohort present with developmental delay and a neuro-behavioral phenotype, individuals with a pathogenic variant in the seventh spectrin repeat have a more severe ID associated with macrocephaly than do most individuals with GEFD1 variants, who display milder ID and microcephaly. Functional studies show that the spectrin and GEFD1 variants cause a TRIO-mediated hyper- or hypo-activation of RAC1, respectively, and we observe a striking correlation between RAC1 activation levels and the head size of the affected individuals. In addition, truncations in TRIO GEFD1 in the vertebrate model X. tropicalis induce defects that are concordant with the human phenotype. This work demonstrates distinct clinical and molecular disorders clustering in the GEFD1 and seventh spectrin repeat domains and highlights the importance of tight control of TRIO-RAC1 signaling in neuronal development., (Copyright © 2020 The Authors. Published by Elsevier Inc. All rights reserved.)

Introduction: Cloacal malformations, a confluence of the urinary tract, vagina and rectum into a single common channel, has a broad and complex anatomic spectrum requiring an imaging tool for visualization, measurement, and surgical planning for the reconstruction of these structures. We evaluated the role of 3-D fluoroscopy for this purpose, as it offers a combination of spatial correlation with precise anatomic measurements., Methods: We examined our imaging protocol for patients with a cloacal malformation and report our experience with rotational fluoroscopy and 3-D reconstruction in 16 consecutive patients referred for cloacal reconstruction. The length of the common channel (CC), the length of the urethra from the bladder neck to the common channel, and the height (and existence or absence) of a vagina or vaginas were determinants of the surgical procedures used for the repair., Results: We performed 16 consecutive 3-D cloacagrams (age range 4 months to 9 years) using a new protocol (Figure 1) that provided the following data which helped with surgical planning: Gynecologic: 3 cases with a single vagina, 5 cases with a duplicated Mullerian system (3 of which were asymmetric) and 2 cases with high vaginas requiring vaginal replacement. Colorectal: Four had a high rectum requiring an abdominal approach, and 6 had a rectum reachable via a posterior sagittal approach. Urologic: Two ectopic ureters requiring reimplantation, 3 patients had vesicoureteral reflux (1 bilateral, 2 unilateral), 1 patient had no bladder, and 7 had a normal sized bladder. Common channel length and urethral length were demonstrated in all cases and used to decide between a total urogenital mobilization or a separation of vagina(s) from the common channel, urogenital separation., Conclusion: The 3-D cloacagram can help predict the surgical plan for urologic, gynecologic, and colorectal components of the cloacal repair. It can predict the CC length as well as the length of the urethra. It helps with predicting the need for vaginal replacement and whether an abdominal approach is needed for the rectum. Its effectiveness is based on the ability to adequately distend structures and see their distal most extent, an advantage over other modalities such as MRI. Added benefits (particularly from the 3D view) include a better spatial understanding of the defect and the diagnosis of concomitant urological abnormalities such as vesicoureteral reflux and ectopic ureters. Disadvantages to this procedure include the need for general anesthesia and a higher exposure to radiation., Level of Evidence: 3., (Copyright © 2019 Elsevier Inc. All rights reserved.)

By using exome sequencing and a gene matching approach, we identified de novo and inherited pathogenic variants in KDM3B in 14 unrelated individuals and three affected parents with varying degrees of intellectual disability (ID) or developmental delay (DD) and short stature. The individuals share additional phenotypic features that include feeding difficulties in infancy, joint hypermobility, and characteristic facial features such as a wide mouth, a pointed chin, long ears, and a low columella. Notably, two individuals developed cancer, acute myeloid leukemia and Hodgkin lymphoma, in childhood. KDM3B encodes for a histone demethylase and is involved in H3K9 demethylation, a crucial part of chromatin modification required for transcriptional regulation. We identified missense and truncating variants, suggesting that KDM3B haploinsufficiency is the underlying mechanism for this syndrome. By using a hybrid facial-recognition model, we show that individuals with a pathogenic variant in KDM3B have a facial gestalt, and that they show significant facial similarity compared to control individuals with ID. In conclusion, pathogenic variants in KDM3B cause a syndrome characterized by ID, short stature, and facial dysmorphism., (Copyright © 2019 American Society of Human Genetics. All rights reserved.)

Purpose: Pathogenic variants in KAT6A have recently been identified as a cause of syndromic developmental delay. Within 2 years, the number of patients identified with pathogenic KAT6A variants has rapidly expanded and the full extent and variability of the clinical phenotype has not been reported., Methods: We obtained data for patients with KAT6A pathogenic variants through three sources: treating clinicians, an online family survey distributed through social media, and a literature review., Results: We identified 52 unreported cases, bringing the total number of published cases to 76. Our results expand the genotypic spectrum of pathogenic variants to include missense and splicing mutations. We functionally validated a pathogenic splice-site variant and identified a likely hotspot location for de novo missense variants. The majority of clinical features in KAT6A syndrome have highly variable penetrance. For core features such as intellectual disability, speech delay, microcephaly, cardiac anomalies, and gastrointestinal complications, genotype- phenotype correlations show that late-truncating pathogenic variants (exons 16-17) are significantly more prevalent. We highlight novel associations, including an increased risk of gastrointestinal obstruction., Conclusion: Our data expand the genotypic and phenotypic spectrum for individuals with genetic pathogenic variants in KAT6A and we outline appropriate clinical management.

Background/purpose: We conduct an annual medical mission to Hospital Ruth Paz para Niños Quemados y Cirugía Pediátrica in Honduras to operate on cases of anorectal malformations (ARM). To improve our knowledge of these patients, we compared their health-related quality of life (HRQoL), and the health literacy of their caregivers from this hospital and ours in the United States., Methods: The BRIEF Health Literacy Screen (BHLS) and Pediatric Quality of Life Inventory 4.0 (PedsQL) were used, respectively, to assess the health literacy and HRQoL of their guardians. All patients scheduled for an ARM-related operation in October 2016 were eligible for inclusion, and a matched population was selected in Nationwide Children's Hospital, Columbus, Ohio., Results: The sample comprised 127 patients, with 22 from Honduras and 105, the US. About 13.6% and 80% of Honduran and American caregivers, respectively, had adequate literacy. Honduran and American caregivers of patients aged 12 months and below rated the HRQoL of their children at 87 and 82, respectively; aged between two and four years, at 84 and 77; aged between two and four years, at 85 and 79; and of teens, at 59 and 66. For adults, the rate was 71 and 77 in Honduras and the US, respectively., Conclusion: Although health literacy is extremely low in the Honduran group, its HRQoL was comparable to that of its American counterpart. Improving health literacy by educating caregivers could be an additional goal for medical missions in the future., Level of Evidence: Level III., (Copyright © 2018 Elsevier Inc. All rights reserved.)

Background: Published health-care costs related to constipation in children in the USA are estimated at $3.9 billion/year. We sought to assess the effect of a bowel management program (BMP) on health-care utilization and costs., Methods: At two collaborating centers, BMP involves an outpatient week during which a treatment plan is implemented and objective assessment of stool burden is performed with daily radiography. We reviewed all patients with severe functional constipation who participated in the program from March 2011 to June 2015 in center 1 and from April 2014 to April 2016 in center 2. ED visits, hospital admissions, and constipation-related morbidities (abdominal pain, fecal impaction, urinary retention, urinary tract infections) 12 months before and 12 months after completion of the BMP were recorded., Results: One hundred eighty-four patients were included (center 1 = 96, center 2 = 88). Sixty-three (34.2%) patients had at least one unplanned visit to the ED before treatment. ED visits decreased to 23 (12.5%) or by 64% (p < 0.0005). Unplanned hospital admissions decreased from 65 to 28, i.e., a 56.9% reduction (p < 0.0005)., Conclusion: In children with severe functional constipation, a structured BMP decreases unplanned visits to the ED, hospital admissions, and costs for constipation-related health care., Level of Evidence: 3., (Copyright © 2018. Published by Elsevier Inc.)

Introduction: Health literacy is low in an estimated one-third of the US population. Little is known about the health literacy of caregivers of children with colorectal conditions. The objective of this study was to investigate whether a timed health literacy intervention could improve health literacy in this population., Methods: We used the BRIEF Health Literacy screening (BHLS) tool on caregivers of children who came to our colorectal clinic. Health literacy was categorized as inadequate, marginal, or adequate. The number of caregivers with adequate health literacy was compared to the number of clinic visits and socioeconomic status., Results: We included 233 caregivers. The average number of clinic visits was 3.5 over 1.2years. At the first clinic visit, 70% (n=98) of caregivers had "adequate" health literacy. Scores improved to 88% (p=0.024) after the fourth visit. Socioeconomic factors were not associated with health literacy. Patients of caregivers with "adequate" health literacy visited our clinic 3.8 times, compared to 2.7 times for those with lower literacy (p=0.006)., Conclusion: Emphasis on providing an education-based approach at each visit increased health literacy significantly. As expected, health literacy was lowest during the first visit, which we believe is the optimal time to implement educational interventions., Type of Study: Case Control/Retrospective Comparative Study., Level of Evidence: Level III., (Copyright © 2017. Published by Elsevier Inc.)