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Individuals with obesity caused by biallelic pathogenic LEPR (leptin receptor) variants can benefit from setmelanotide, the novel MC4R agonist. An ongoing phase 3 clinical trial (NCT05093634) includes individuals with obesity who carry a heterozygous LEPR variant, although the obesogenic impact of these variants remains incompletely evaluated. The aim of this study was to functionally assess heterozygous variants in LEPR and to evaluate their effect on obesity. We sequenced LEPR in ∼10,000 participants from the French RaDiO study. We found 86 rare heterozygous variants. Each identified variant was then investigated in vitro using luciferase and western blot assays. Using the criteria of the American College of Medical Genetics and Genomics (ACMG), including the strong criterion related to functional assays, we found 12 pathogenic LEPR variants. Most heterozygotes did not present with obesity, and we found no association between these pathogenic variants and body mass index (BMI). This lack of association between pathogenic LEPR variants and obesity risk or BMI was confirmed using exome data from 200,000 individuals in the UK Biobank. In the literature, among 55 reported heterozygotes for of a rare pathogenic LEPR variant, only 27% had obesity. In conclusion, monoallelic pathogenic LEPR variants were functionally tested, and they do not elevate the risk of obesity or BMI levels. This raises questions about the use of setmelanotide, a costly drug with potential side effects, based solely on the presence of a heterozygous LEPR variant., Competing Interests: Declaration of interests The authors declare no competing interests., (Copyright © 2024 American Society of Human Genetics. Published by Elsevier Inc. All rights reserved.)

Functional genetics has identified drug targets for metabolic disorders. Opioid use impacts metabolic homeostasis, although mechanisms remain elusive. Here, we explore the OPRD1 gene (encoding delta opioid receptor, DOP) to understand its impact on type 2 diabetes. Large-scale sequencing of OPRD1 and in vitro analysis reveal that loss-of-function variants are associated with higher adiposity and lower hyperglycemia risk, whereas gain-of-function variants are associated with lower adiposity and higher type 2 diabetes risk. These findings align with studies of opium addicts. OPRD1 is expressed in human islets and beta cells, with decreased expression under type 2 diabetes conditions. DOP inhibition by an antagonist enhances insulin secretion from human beta cells and islets. RNA-sequencing identifies pathways regulated by DOP antagonism, including nerve growth factor, circadian clock, and nuclear receptor pathways. Our study highlights DOP as a key player between opioids and metabolic homeostasis, suggesting its potential as a therapeutic target for type 2 diabetes., (© 2024. The Author(s).)

Adolescence is a strategic developmental stage in terms of preventing later difficulties and ensuring good mental health. Prophylactic interventions, which are conducted before the onset, prolongation, or worsening of difficulties, and aim to prevent or reduce symptoms or to promote wellbeing, therefore appear particularly appropriate for adolescents. However, existing prophylactic interventions conducted with adolescents have several weaknesses, including sparse theoretical frameworks, ambivalent evidence of their efficacy, and implementation and dissemination difficulties. In addition, no data are currently available on the effectiveness of such interventions in France. To fill this gap, a four-arm randomized controlled trial will be performed to assess the effectiveness of three prophylactic interventions targeting reactive, proactive and interpersonal adaptation in fourth-grade middle-school students, together with participants' experience and perception of the interventions. Based on existing knowledge about adolescents, their learning mechanisms, and field constraints, these three interventions have been designed to promote their learning and receptiveness to interventions. Compared with baseline (i.e., before the intervention), we expect to observe a significant decrease in the level of distress (anxiety and depressive symptoms, functional impairment, and psychosocial difficulties) and a significant increase in the level of wellbeing after the intervention, across the three intervention groups, but not in the control group. In addition, we expect to observe post-intervention improvements in the processes targeted by the reactive adaptation intervention (operationalized as coping strategy use and flexibility), those targeted by the proactive adaptation intervention (operationalized as the tendency to engage in committed actions and general self-efficacy), and those targeted by the interpersonal adaptation intervention (operationalized as assertiveness in interactions), but only in the corresponding groups, with no change in any of these processes in the control group. The results of this research will not only enrich our knowledge of the processes involved in adolescents' distress and wellbeing, but also provide clues as to the best targets for intervention. Moreover, the material for these interventions will be freely available in French on request to the corresponding author, providing access to innovative and fully assessed interventions aimed at promoting adolescents' mental health in France.This clinical trial is currently being registered under no. 2023-A01973-42 on https://ansm.sante.fr/ . This is the first version of the protocol., (© 2024. The Author(s).)

Background: Immuno-radiotherapy may improve outcomes for patients with advanced solid tumors, although optimized combination modalities remain unclear. Here, we report the colorectal (CRC) cohort analysis from the SABR-PDL1 trial that evaluated the PD-L1 inhibitor atezolizumab in combination with stereotactic body radiation therapy (SBRT) in advanced cancer patients., Methods: Eligible patients received atezolizumab 1200 mg every 3 weeks until progression or unmanageable toxicity, together with ablative SBRT delivered concurrently with the 2nd cycle (recommended dose of 45 Gy in 3 fractions, adapted upon normal tissue tolerance constraint). SBRT was delivered to at least one tumor site, with at least one additional measurable lesion being kept from the radiation field. The primary efficacy endpoint was one-year progression-free survival (PFS) rate from the start of atezolizumab. Sequential tumor biopsies were collected for deep multi-feature immune profiling., Results: Sixty pretreated (median of 2 prior lines) advanced CRC patients (38 men [63%]; median age, 59 years [range, 20-81 years]; 77% with liver metastases) were enrolled in five centers (France: n = 4, Spain: n = 1) from 11/2016 to 04/2019. All but one (98%) received atezolizumab and 54/60 (90%) received SBRT. The most frequently irradiated site was lung (n = 30/54; 56.3%). Treatment-related G3 (no G4-5) toxicity was observed in 3 (5%) patients. Median OS and PFS were respectively 8.4 [95%CI:5.9-11.6] and 1.4 months [95%CI:1.2-2.6], including five (9%) patients with PFS > 1 year (median time to progression: 19.2 months, including 2/5 MMR-proficient). Best overall responses consisted of stable disease (n = 38; 64%), partial (n = 3; 5%) and complete response (n = 1; 2%). Immune-centric multiplex IHC and RNAseq showed that SBRT redirected immune cells towards tumor lesions, even in the case of radio-induced lymphopenia. Baseline tumor PD-L1 and IRF1 nuclear expression (both in CD3 + T cells and in CD68 + cells) were higher in responding patients. Upregulation of genes that encode for proteins known to increase T and B cell trafficking to tumors (CCL19, CXCL9), migration (MACF1) and tumor cell killing (GZMB) correlated with responses., Conclusions: This study provides new data on the feasibility, efficacy, and immune context of tumors that may help identifying advanced CRC patients most likely to respond to immuno-radiotherapy., Trial Registration: EudraCT N°: 2015-005464-42; Clinicaltrial.gov number: NCT02992912., (© 2024. The Author(s).)

Objective: Rare variants in DYRK1B have been described in some patients with central obesity, type 2 diabetes, and early-onset coronary disease. Owing to the limited number of conducted studies, the broader impact of DYRK1B variants on a larger scale has yet to be investigated., Research Design and Methods: DYRK1B was sequenced in 9,353 participants from a case-control study for obesity and type 2 diabetes. Each DYRK1B variant was functionally assessed in vitro. Variant pathogenicity was determined using criteria from the American College of Medical Genetics and Genomics (ACMG). The effect of pathogenic or likely pathogenic (P/LP) variants on metabolic traits was assessed using adjusted mixed-effects score tests., Results: Sixty-five rare, heterozygous DYRK1B variants were identified and were not associated with obesity or type 2 diabetes. Following functional analyses, 20 P/LP variants were pinpointed, including 6 variants that exhibited a fully inhibitory effect (P/LP-null) on DYRK1B activity. P/LP and P/LP-null DYRK1B variants were associated with increased BMI and obesity risk; however, the impact was notably more pronounced for the P/LP-null variants (effect of 8.0 ± 3.2 and odds ratio of 7.9 [95% CI 1.2-155]). Furthermore, P/LP-null variants were associated with higher fasting glucose and type 2 diabetes risk (effect of 2.9 ± 1.0 and odds ratio of 4.8 [95% CI 0.85-37]), while P/LP variants had no effect on glucose homeostasis., Conclusions: P/LP, total loss-of-function DYRK1B variants cause monogenic obesity associated with type 2 diabetes. This study underscores the significance of conducting functional assessments in order to accurately ascertain the tangible effects of P/LP DYRK1B variants., (© 2024 by the American Diabetes Association.)

Background: There is ample evidence that most children do not perform enough physical activity (PA). To address this major public health problem, the French government implemented 30 minutes of daily PA (DPA) at schools but did not provide any supplemental resources or concrete guidance. Considering both children's interest in video games and the need for teachers to complete their curriculum, the use of a learning-based exergame that combines PA and learning appears particularly relevant., Objective: The first objective of this study was to evaluate the feasibility of implementing 30 minutes of DPA through exergaming among school-age children. The second objective was to examine the effects of an exergaming program on physical literacy, academic learning, and soft skills (motivation, self-efficacy, and concentration)., Methods: This interventional study had a pre-post design and used the Play LÜ exergame platform. The study included 79 children with a mean age of 8.9 (SD 1.2) years from grade 2 (7 years old) to grade 5 (11 years old). Play LÜ requires players to throw balls against a wall to reach a target or to activate an object and provides an interactive game area for educational activities linked to specific learning themes. After a 4-session familiarization phase during which the teachers chose to prioritize mathematics learning in 30-minute DPA sessions, students took part in DPA sessions over a period of 3 weeks with Play LÜ and a motor skills circuit behind the LÜ setup to keep them continuously active. All sessions were carried out by PA specialists. Each session started with a warm-up using the Grööve application, continued with main activities promoting mathematics learning adapted to each grade level, and ended with a 3-minute meditation for returning to a calm and serene state using the Gaïa application. Before (T0) and after (T1) the program, students completed a self-evaluation booklet to assess their levels of physical literacy, academic performance, and soft skills., Results: The implementation of this exergaming program was welcomed by the school's administration, teaching staff, and parents. After the program, we observed increased scores for physical literacy (difference +2.6, percentage change +3.6%; W=933.0; P=.002; r rb =-0.39, 95% CI -0.58 to -0.16) and motivation in mathematics (+0.7, +9.8%; W=381.5; P=.005; r rb =-0.44, 95% CI -0.66 to -0.16). In addition, it is important to note that some measures progressed differently across learning levels and age groups., Conclusions: The study results indicate positive impacts of learning-based exergaming on physical literacy and motivation in mathematics among school-age children., (©Aurelie Goncalves, Florence Lespiau, Gaëtan Briet, Eugénie Vaillant-Coindard, Angèle Palermo, Elsa Decobert, Nathan Allegret-Bourdon, Elodie Charbonnier. Originally published in JMIR Serious Games (https://games.jmir.org), 23.02.2024.)

Aims/hypothesis: GLIS3 encodes a transcription factor involved in pancreatic beta cell development and function. Rare pathogenic, bi-allelic mutations in GLIS3 cause syndromic neonatal diabetes whereas frequent SNPs at this locus associate with common type 2 diabetes risk. Because rare, functional variants located in other susceptibility genes for type 2 diabetes have already been shown to strongly increase individual risk for common type 2 diabetes, we aimed to investigate the contribution of rare pathogenic GLIS3 variants to type 2 diabetes., Methods: GLIS3 was sequenced in 5471 individuals from the Rare Variants Involved in Diabetes and Obesity (RaDiO) study. Variant pathogenicity was assessed following the criteria established by the American College of Medical Genetics and Genomics (ACMG). To address the pathogenic strong criterion number 3 (PS3), we conducted functional investigations of these variants using luciferase assays, focusing on capacity of GLIS family zinc finger 3 (GLIS3) to bind to and activate the INS promoter. The association between rare pathogenic or likely pathogenic (P/LP) variants and type 2 diabetes risk (and other metabolic traits) was then evaluated. A meta-analysis combining association results from RaDiO, the 52K study (43,125 individuals) and the TOPMed study (44,083 individuals) was finally performed., Results: Through targeted resequencing of GLIS3, we identified 105 rare variants that were carried by 395 participants from RaDiO. Among them, 49 variants decreased the activation of the INS promoter. Following ACMG criteria, 18 rare variants were classified as P/LP, showing an enrichment in the last two exons compared with the remaining exons (p<5×10 -6 ; OR>3.5). The burden of these P/LP variants was strongly higher in individuals with type 2 diabetes (p=3.0×10 -3 ; OR 3.9 [95% CI 1.4, 12]), whereas adiposity, age at type 2 diabetes diagnosis and cholesterol levels were similar between variant carriers and non-carriers with type 2 diabetes. Interestingly, all carriers with type 2 diabetes were sensitive to oral sulfonylureas. A total of 7 P/LP variants were identified in both 52K and TOPMed studies. The meta-analysis of association studies obtained from RaDiO, 52K and TOPMed showed an enrichment of P/LP GLIS3 variants in individuals with type 2 diabetes (p=5.6×10 -5 ; OR 2.1 [95% CI 1.4, 2.9])., Conclusions/interpretation: Rare P/LP GLIS3 variants do contribute to type 2 diabetes risk. The variants located in the distal part of the protein could have a direct effect on its functional activity by impacting its transactivation domain, by homology with the mouse GLIS3 protein. Furthermore, rare P/LP GLIS3 variants seem to have a direct clinical effect on beta cell function, which could be improved by increasing insulin secretion via the use of sulfonylureas., (© 2023. The Author(s).)

Objective: Human functional genomics has proven powerful in discovering drug targets for common metabolic disorders. Through this approach, we investigated the involvement of the purinergic receptor P2RY1 in type 2 diabetes (T2D)., Methods: P2RY1 was sequenced in 9,266 participants including 4,177 patients with T2D. In vitro analyses were then performed to assess the functional effect of each variant. Expression quantitative trait loci (eQTL) analysis was performed in pancreatic islets from 103 pancreatectomized individuals. The effect of P2RY1 on glucose-stimulated insulin secretion was finally assessed in human pancreatic beta cells (EndoCβH5), and RNA sequencing was performed on these cells., Results: Sequencing P2YR1 in 9,266 participants revealed 22 rare variants, seven of which were loss-of-function according to our in vitro analyses. Carriers, except one, exhibited impaired glucose control. Our eQTL analysis of human islets identified P2RY1 variants, in a beta-cell enhancer, linked to increased P2RY1 expression and reduced T2D risk, contrasting with variants located in a silent region associated with decreased P2RY1 expression and increased T2D risk. Additionally, a P2RY1-specific agonist increased insulin secretion upon glucose stimulation, while the antagonist led to decreased insulin secretion. RNA-seq highlighted TXNIP as one of the main transcriptomic markers of insulin secretion triggered by P2RY1 agonist., Conclusion: Our findings suggest that P2RY1 inherited or acquired dysfunction increases T2D risk and that P2RY1 activation stimulates insulin secretion. Selective P2RY1 agonists, impermeable to the blood-brain barrier, could serve as potential insulin secretagogues., Competing Interests: Declaration of competing interest Authors declare that they have no competing interests., (Copyright © 2023 The Authors. Published by Elsevier GmbH.. All rights reserved.)

Objective: Heterozygous pathogenic or likely pathogenic (P/LP) PDX1 variants cause monogenic diabetes. We comprehensively examined the phenotypes of carriers of P/LP PDX1 variants, and delineated potential treatments that could be efficient in an objective of precision medicine., Methods: The study primarily involved a family harboring a novel P/LP PDX1 variant. We then conducted an analysis of documented carriers of P/LP PDX1 variants, from the Human Gene Mutation Database (HGMD), RaDiO study, and Type 2 Diabetes Knowledge Portal (T2DKP) including 87 K participants., Results: Within the family, we identified a P/LP PDX1 variant encoding p.G232S in four relatives. All of them exhibited diabetes, albeit with very different ages of onset (10-40 years), along with caudal pancreatic agenesis and childhood-onset obesity. In the HGMD, 79 % of carriers of a P/LP PDX1 variant displayed diabetes (with differing ages of onset from eight days of life to 67 years), 63 % exhibited pancreatic insufficiency and surprisingly 40 % had obesity. The impact of P/LP PDX1 variants on increased risk of type 2 diabetes mellitus was confirmed in the T2DKP. Dipeptidyl peptidase 4 inhibitor (DPP4i) and glucagon-like peptide-1 receptor agonist (GLP1-RA), enabled good glucose control without hypoglycemia and weight management., Conclusions: This study reveals diverse clinical presentations among the carriers of a P/LP PDX1 variant, highlighting strong variations in diabetes onset, and unexpectedly high prevalence of obesity and pancreatic development abnormalities. Clinical data suggest that DPP4i and GLP1-RA may be the best effective treatments to manage both glucose and weight controls, opening new avenue in precision diabetic medicine., Competing Interests: Declaration of competing interest Authors declare that they have no competing interests., (Copyright © 2023 Elsevier Masson SAS. All rights reserved.)

Aim: To investigate spoken language comprehension (SLC), single-word comprehension (SWC), functional communication development, and their determinants, in children with cerebral palsy., Method: This was a prospective cohort study in the Netherlands spanning 2 years 6 months. The main outcomes were SLC and SWC, assessed by the Computer-Based instrument for Low motor Language Testing (C-BiLLT) and the Peabody Picture Vocabulary Test-III-NL (PPVT-III-NL) respectively; and functional communication, measured by a subscale of the Focus on the Outcomes of Communication Under Six-34 (FOCUS-34). Linear mixed models were used to determine developmental trajectories, which were compared with norm and reference data. Potential determinants, for example intellectual functions, speech production, functional communication level (classified with the Communication Function Classification System, CFCS), and functional mobility, were added to assess their effects., Results: Children with cerebral palsy (n = 188; mean age 59 months, range 17-110) were monitored for 2 years 6 months. Developmental trajectories for SLC (C-BiLLT) and SWC (PPVT-III-NL) were nonlinear; those for functional communication (FOCUS-34) were linear. Compared with norm and reference groups, significantly delayed SLC, SWC, and functional communication development were found. Determinants for SLC and SWC were intellectual functions and functional communication level (CFCS); and for functional communication development (FOCUS-34), speech production and arm-hand functioning., Interpretation: Children with cerebral palsy showed delayed SLC, SWC, and functional communication development compared with norm and reference groups. Remarkably, functional mobility was not associated with the development of SLC, SWC, or functional communication., What This Paper Adds: Children with cerebral palsy have delayed spoken language comprehension (SLC), single-word comprehension (SWC), and functional communication development, compared to norm and reference data. Determinants for SLC and SWC development are intellectual functions and functional communication level. Determinants for functional communication development are speech production and arm-hand functioning. Functional mobility is not associated with SLC, SWC, or functional communication., (© 2023 The Authors. Developmental Medicine & Child Neurology published by John Wiley & Sons Ltd on behalf of Mac Keith Press.)

Introduction: This document is a summary of the French intergroup guidelines regarding the management of esophageal cancer (EC) published in July 2022, available on the website of the French Society of Gastroenterology (SNFGE) (www.tncd.org)., Methods: This collaborative work was conducted under the auspices of several French medical and surgical societies involved in the management of EC. Recommendations were graded in three categories (A, B and C), according to the level of evidence found in the literature until April 2022., Results: EC diagnosis and staging evaluation are mainly based on patient's general condition assessment, endoscopy plus biopsies, TAP CT-scan and 18F FDG-PET. Surgery alone is recommended for early-stage EC, while locally advanced disease (N+ and/or T3-4) is treated with perioperative chemotherapy (FLOT) or preoperative chemoradiation (CROSS regimen) followed by immunotherapy for adenocarcinoma. Preoperative chemoradiation (CROSS regimen) followed by immunotherapy or definitive chemoradiation with the possibility of organ preservation are the two options for squamous cell carcinoma. Salvage surgery is recommended for incomplete response or recurrence after definitive chemoradiation and should be performed in an expert center. Treatment for metastatic disease is based on systemic therapy including chemotherapy, immunotherapy or combined targeted therapy according to biomarkers testing such as HER2 status, MMR status and PD-L1 expression., Conclusion: These guidelines are intended to provide a personalised therapeutic strategy for daily clinical practice and are subject to ongoing optimization. Each individual case should be discussed by a multidisciplinary team., Competing Interests: Conflict of interest O. Bouché: Amgen, Apmonia Therapeutics, Bayer, Deciphera, Merck KGaA, MSD, Pierre Fabre, Servier. T. Aparicio: Amgen, Servier, Pierre Fabre, MSD, BMS, SIRTEC T. Voron : BMS Maximilien Barret: Olympus, Pentax, Medtronic, Dr Falk Pharma, Norgine D. Tougeron: Amgen, Roche, Servier, Pierre Fabre, Merck KGaA, MSD, BMS, Astra Zeneca. The other authors have reported no conflicts of interest., (Copyright © 2023. Published by Elsevier Ltd.)

We previously demonstrated that 50% of children with obesity from consanguineous families from Pakistan carry pathogenic variants in known monogenic obesity genes. Here, we have discovered a novel monogenetic recessive form of severe childhood obesity using an in-house computational staged approach. The analysis included whole-exome sequencing data of 366 children with severe obesity, 1,000 individuals of the Pakistan Risk of Myocardial Infarction Study (PROMIS) study, and 200,000 participants of the UK Biobank to prioritize genes harboring rare homozygous variants with putative effect on human obesity. We identified five rare or novel homozygous missense mutations predicted deleterious in five consanguineous families in P4HTM encoding prolyl 4-hydroxylase transmembrane (P4H-TM). We further found two additional homozygous missense mutations in children with severe obesity of Indian and Moroccan origin. Molecular dynamics simulation suggested that these mutations destabilized the active conformation of the substrate binding domain. Most carriers also presented with hypotonia, cognitive impairment, and/or developmental delay. Three of the five probands died of pneumonia during the first 2 years of the follow-up. P4HTM deficiency is a novel form of syndromic obesity, affecting 1.5% of our children with obesity associated with high mortality. P4H-TM is a hypoxia-inducible factor that is necessary for survival and adaptation under oxygen deprivation, but the role of this pathway in energy homeostasis and obesity pathophysiology remains to be elucidated., (© 2023 by the American Diabetes Association.)

Purpose: To identify determinants of spoken language comprehension (SLC) in children with cerebral palsy (CP)., Materials and Methods: Cross-sectional data of 207 children with CP were included: 82 toddlers (18 months-3;11 years), 59 preschool children (4;0-5;11 years), and 66 schoolchildren (6;0-8;11 years), across all Gross Motor Function Classification System (GMFCS) levels. SLC was assessed using the Computer-Based instrument for Low motor Language Testing (C-BiLLT). Potential determinants were retrieved from medical files and through parental questionnaires. Per developmental stage, multivariable regression analyses were used to assess determinants of SLC., Results: Fifty-nine percent of the children showed below average SLC. Significant determinants for SLC differed per developmental stage. In toddlers: age, motor type, functional communication and speech function ( R 2 = 0.637); in preschool children: functional communication, speech function and language activities ( R 2 = 0.820), and in schoolchildren: functional communication, intellectual functioning and arm-hand functioning ( R 2 = 0.807). For all developmental stages, functional mobility was not a significant determinant., Conclusions: A large proportion of children with CP across all GMFCS levels have SLC impairments. Findings indicate that SLC is strongly determined by functional communication classified with CFCS. We recommend standardized assessment and monitoring of SLC in all children with CP. IMPLICATIONS FOR REHABILITATIONChildren across all GMFCS levels can experience difficulties in spoken language comprehension.At all developmental stages, functional communication (classified with CFCS) is an important determinant of spoken language comprehension.Standardized assessment and monitoring of spoken language comprehension, language production, speech, and communication of all children with CP, is strongly recommended.When children show below average performances, especially in spoken language comprehension, intervening with speech and language therapy and guidance for parents, is advised.

Purpose: The Viking Speech Scale is used to classify speech performance in children with cerebral palsy (CP). A Dutch-language version (VSS-NL) has recently become available. This study aimed to determine the reliability and validity of the VSS-NL and the association with motor type of CP, Gross Motor Function Classification System (GMFCS), Manual Ability Classification System (MACS) and Communication Function Classification System (CFCS)., Methods: A total of 90 children with CP, recruited throughout the Netherlands, took part in the study. VSS-NL classifications by speech and language therapists unfamiliar (SLT1) and familiar (SLT2) with the child, parents and physicians were compared. Convergent and discriminant validity were determined with the Intelligibility in Context Scale-Dutch (ICS-NL) and the Computer Based Instrument for Low Motor Language Testing (C-BiLLT). Inter- and intrarater reliability were determined by weighted Kappa (ƙ w ). Validity and associations between VSS-NL and GMFCS, MACS and CFCS were determined with Spearman's coefficient. Association between VSS-NL and motor type of CP was determined with Fisher's exact test., Results: Interrater reliability was excellent between SLT1-SLT2 (ƙ w  = 0.93, 95% confidence interval [CI] 0.87-0.99), good between SLT1-parent (ƙ w  = 0.71, 95% CI 0.60-0.83), SLT1-physician (ƙ w  = 0.70, 95% CI 0.58-0.81), SLT2-parent (ƙ w  = 0.71, 95% CI 0.57-0.84), SLT2-physician (ƙ w  = 0.73, 95% CI 0.62-0.85) and parent-physician (ƙ = 0.72, 95% CI 0.60-0.85). Intrarater reliability was excellent for SLTs familiar and unfamiliar to the child (ƙ w  = 1.00, 95% CI 1.00-1.00), and very good for physicians (ƙ w  = 0.89, 95% CI 0.75-1.00) and parents (ƙ w  = 0.72, 95% CI 0.62-1.00). Convergent validity was very strong (r = -0.81, p < 0.001) and discriminant validity moderate (r = -0.56, p < 0.001). Association with motor type of CP was significant (χ 2  = 27.558, p < 0.001) and strong with GMFCS (r = 0.62, p < 0.001), MACS (r = 0.63, p < 0.01) and CFCS (r = 0.69, p < 0.001)., Conclusion: The VSS-NL is a reliable and valid system to classify speech performance in children with cerebral palsy. Classifications can be performed by SLTs, parents and physicians., (© 2022 The Authors. Child: Care, Health and Development published by John Wiley & Sons Ltd.)