CUL3-related neurodevelopmental disorder: Clinical phenotype of 20 new individuals and identification of a potential phenotype-associated episignature.

Neurodevelopmental disorder with or without autism or seizures (NEDAUS) is a neurodevelopmental disorder characterized by global developmental delay, speech delay, seizures, autistic features, and/or behavior abnormalities. It is caused by CUL3 (Cullin-3 ubiquitin ligase) haploinsufficiency. We collected clinical and molecular data from 26 individuals carrying pathogenic variants and variants of uncertain significance (VUS) in the CUL3 gene, including 20 previously unreported cases.

Phenotypic spectrum in Weiss-Kruszka syndrome caused by ZNF462 variants: Three new patients and literature review.

Weiss-Kruszka Syndrome (WSKA) is caused by pathogenic variants in ZNF462 representing a rare autosomal dominant congenital anomaly syndrome. It is characterized by global developmental delay, hypotonia, feeding difficulties, and craniofacial abnormalities, documented in fewer than 30 patients. ZNF462, located on chromosome 9p31.

PSMD11 loss-of-function variants correlate with a neurobehavioral phenotype, obesity, and increased interferon response.

Primary proteasomopathies have recently emerged as a new class of rare early-onset neurodevelopmental disorders (NDDs) caused by pathogenic variants in the PSMB1, PSMC1, PSMC3, or PSMD12 proteasome genes. Proteasomes are large multi-subunit protein complexes that maintain cellular protein homeostasis by clearing ubiquitin-tagged damaged, misfolded, or unnecessary proteins. In this study, we have identified PSMD11 as an additional proteasome gene in which pathogenic variation is associated with an NDD-causing proteasomopathy.

Clinical phenotypes of adults with monogenic and syndromic genetic obesity.

Objective: Considering limited evidence on diagnostics of genetic obesity in adults, we evaluated phenotypes of adults with genetic obesity. Additionally, we assessed the applicability of Endocrine Society (ES) recommendations for genetic testing in pediatric obesity.

Methods: We compared clinical features, including age of onset of obesity and appetite, between adults with non-syndromic monogenic obesity (MO), adults with syndromic obesity (SO), and adults with common obesity (CO) as control patients.

Evaluation of 100 Dutch cases with 16p11.2 deletion and duplication syndromes; from clinical manifestations towards personalized treatment options.

The 16p11.2 deletion syndrome is a clinically heterogeneous disorder, characterized by developmental delay, intellectual disability, hyperphagia, obesity, macrocephaly and psychiatric problems. Cases with 16p11.

GNB1 and obesity: Evidence for a correlation between haploinsufficiency and syndromic obesity.

Most patients with GNB1 encephalopathy have developmental delay and/or intellectual disability, brain anomalies and seizures. Recently, two cases with GNB1 encephalopathy caused by haploinsufficiency have been reported that also show a Prader-Willi-like phenotype of childhood hypotonia and severe obesity. Here we present three new cases from our expert centre for genetic obesity in which GNB1 truncating and splice variants, probably leading to haploinsufficiency, were identified.

Developmental epileptic encephalopathy in DLG4-related synaptopathy.

Objective: The postsynaptic density protein of excitatory neurons PSD-95 is encoded by discs large MAGUK scaffold protein 4 (DLG4), de novo pathogenic variants of which lead to DLG4-related synaptopathy. The major clinical features are developmental delay, intellectual disability (ID), hypotonia, sleep disturbances, movement disorders, and epilepsy. Even though epilepsy is present in 50% of the individuals, it has not been investigated in detail.

Delineation of the adult phenotype of Coffin-Siris syndrome in 35 individuals.

Coffin-Siris syndrome (CSS) is a rare multisystemic autosomal dominant disorder. Since 2012, alterations in genes of the SWI/SNF complex were identified as the molecular basis of CSS, studying largely pediatric cohorts. Therefore, there is a lack of information on the phenotype in adulthood, particularly on the clinical outcome in adulthood and associated risks.

Genetic Obesity Disorders: Body Mass Index Trajectories and Age of Onset of Obesity Compared with Children with Obesity from the General Population.

Objective: We sought to assess body mass index trajectories of children with genetic obesity to identify optimal early age of onset of obesity (AoO) cut-offs for genetic screening.

Study Design: This longitudinal, observational study included growth measurements from birth onward of children with nonsyndromic and syndromic genetic obesity and control children with obesity from a population-based cohort. Diagnostic performance of AoO was evaluated.

The Narrative of a Patient with Leptin Receptor Deficiency: Personalized Medicine for a Rare Genetic Obesity Disorder.

Leptin receptor (LEPR) deficiency is a rare genetic disorder that affects the body's ability to regulate appetite and weight. For patients and their families, the disorder seriously disrupts daily life; however, little is published about this impact. We here report the experiences of a 10.

Obesity and Hyperphagia With Increased Defective ACTH: A Novel POMC Variant.

Objective: Patients with pro-opiomelanocortin (POMC) defects generally present with early-onset obesity, hyperphagia, hypopigmentation and adrenocorticotropin (ACTH) deficiency. Rodent models suggest that adequate cleavage of ACTH to α-melanocortin-stimulating hormone (α-MSH) and desacetyl-α-melanocortin-stimulating hormone (d-α-MSH) by prohormone convertase 2 at the KKRR region is required for regulating food intake and energy balance.

Methods: We present 2 sisters with a novel POMC gene variant, leading to an ACTH defect at the prohormone convertase 2 cleavage site, and performed functional studies of this variant.

SOX11 variants cause a neurodevelopmental disorder with infrequent ocular malformations and hypogonadotropic hypogonadism and with distinct DNA methylation profile.

Purpose: This study aimed to undertake a multidisciplinary characterization of the phenotype associated with SOX11 variants.

Methods: Individuals with protein altering variants in SOX11 were identified through exome and genome sequencing and international data sharing. Deep clinical phenotyping was undertaken by referring clinicians.

Impact of the COVID-19 Pandemic and Related Lockdown Measures on Lifestyle Behaviors and Well-Being in Children and Adolescents with Severe Obesity.

Introduction: COVID-19 lockdown measures have large impact on lifestyle behaviors and well-being of children. The aim of this mixed-methods study was to investigate the impact of COVID-19 lockdown measures on eating styles and behaviors, physical activity (PA), screen time, and health-related quality of life (HRQoL) in children (0-18 years) with severe obesity.

Methods: During the first COVID-19 wave (April 2020), validated questionnaires were completed and semi-structured telephone interviews were conducted with parents of children with severe obesity (adult body mass index [BMI]-equivalent ≥35 kg/m2) and/or with the children themselves.

Effects of glucagon-like peptide-1 analogue treatment in genetic obesity: A case series.

Obesity is highly prevalent and comes with serious health burden. In a minority, a genetic cause is present which often results in therapy-resistant obesity. Liraglutide is a glucagon-like peptide-1 (GLP-1) analogue, which has beneficial effects on satiety and weight in common obesity.

DLG4-related synaptopathy: a new rare brain disorder.

Purpose: Postsynaptic density protein-95 (PSD-95), encoded by DLG4, regulates excitatory synaptic function in the brain. Here we present the clinical and genetic features of 53 patients (42 previously unpublished) with DLG4 variants.

Methods: The clinical and genetic information were collected through GeneMatcher collaboration.

Erratum: Identifying underlying medical causes of pediatric obesity: Results of a systematic diagnostic approach in a pediatric obesity center.

[This corrects the article DOI: 10.1371/journal.pone.

Bariatric Surgery for Monogenic Non-syndromic and Syndromic Obesity Disorders.

Purpose Of Review: The global prevalence of obesity has increased rapidly over the last decades, posing a severe threat to human health. Currently, bariatric surgery is the most effective therapy for patients with morbid obesity. It is unknown whether this treatment is also suitable for patients with obesity due to a confirmed genetic defect (genetic obesity disorders).

Who ever heard of 16p11.2 deletion syndrome? Parents' perspectives on a susceptibility copy number variation syndrome.

Chromosomal microarray analysis is an important diagnostic tool to identify copy number variations (CNV). Some of the CNVs affect susceptibility regions, which means that deletions or duplications in these regions have partial penetrance and often give an increased risk for a spectrum of neurocognitive disorders. Not much is known about the impact of rare CNV susceptibility syndromes on the life of patients or their parents.

Identifying underlying medical causes of pediatric obesity: Results of a systematic diagnostic approach in a pediatric obesity center.

Background: Underlying medical causes of obesity (endocrine disorders, genetic obesity disorders, cerebral or medication-induced obesities) are thought to be rare. Even in specialized pediatric endocrinology clinics, low diagnostic yield is reported, but evidence is limited. Identifying these causes is vital for patient-tailored treatment.

Second case of Bardet-Biedl syndrome caused by biallelic variants in IFT74.

Bardet-Biedl syndrome (BBS) is a rare autosomal recessive disorder of the cilia, often resulting in a phenotype of obesity, rod-cone dystrophy, a variable degree of intellectual disability, polydactyly, renal problems, and/or hypogonadism in males or genital abnormalities in females. We here report the case of an 11-year-old girl who presented with postaxial polydactyly, retinal dystrophy, and childhood obesity, suggesting Bardet-Biedl syndrome. She had no renal problems, developmental delay, or intellectual disability.

Functional Analysis of the SIM1 Variant p.G715V in 2 Patients With Obesity.

Context: Single-minded homologue 1 (SIM1) is a transcription factor with several physiological and developmental functions. Haploinsufficiency of SIM1 is associated with early-onset obesity with or without Prader-Willi-like (PWL) features and may exhibit incomplete penetrance.

Case Description: Next-generation sequencing was performed for 2 male patients with obesity, including 1 man presenting with intellectual disability (ID), body mass index (BMI) of 47.