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Validity of the Ages and Stages Questionnaires in Term and Preterm Infants
(2013)
SCHONHAUT BERMAN, LUISA
;
Iván Armijo
;
Marianne Schönstedt
;
Jorge Alvarez
;
Miguel Cordero
<jats:sec> <jats:title>BACKGROUND:</jats:title> <jats:p>This study assessed the concurrent validity of the parent-completed developmental screening measure Ages and Stages Questionnaires, Third Edition (ASQ-3) compared with the Bayley Scales of Infant and Toddler Development, Third Edition (Bayley-III) in children born term, late preterm, or extremely preterm at 8, 18, or 30 months of corrected gestational ages (CGA).</jats:p> </jats:sec> <jats:sec> <jats:title>METHODS:</jats:title> <jats:p>Data were collected from 306 term and preterm children ages 8, 18, and 30 months’ CGA recruited from an ambulatory well-child clinic in Santiago, Chile. Parents completed the ASQ-3 in their homes, and afterward a trained professional administered the Bayley-III in a clinic setting. On the ASQ-3, the presence of any domain screened &lt;2 SDs below the mean area score was considered a positive screen (indicating failure or delay). A Bayley-III score less than ≤1 SD indicated mild or severe delay.</jats:p> </jats:sec> <jats:sec> <jats:title>RESULTS:</jats:title> <jats:p>ASQ-3 showed adequate psychometric properties (75% sensitivity and 81% specificity) and modest agreement with the Bayley-III (r = 0.56). Sensitivity, specificity, and correlations between measures improved with testing age and in children who were born extremely preterm.</jats:p> </jats:sec> <jats:sec> <jats:title>CONCLUSIONS:</jats:title> <jats:p>Considering its psychometric properties, the ASQ-3 can be recommended for routine use in screening low-risk children at 8, 18, and 30 months’ CGA and is advisable to be included in follow-up programs for children with biological risk factors such as those born preterm.</jats:p> </jats:sec>
3Scopus© Citations 249
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<i>SLC6A1</i> variant pathogenicity, molecular function and phenotype: a genetic and clinical analysis
(2023)
Arthur Stefanski
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Eduardo Pérez-Palma
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Tobias Brünger
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Ludovica Montanucci
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Cornelius Gati
<jats:title>Abstract</jats:title> <jats:p>Genetic variants in the SLC6A1 gene can cause a broad phenotypic disease spectrum by altering the protein function. Thus, systematically curated clinically relevant genotype-phenotype associations are needed to understand the disease mechanism and improve therapeutic decision-making.</jats:p> <jats:p>We aggregated genetic and clinical data from 172 individuals with likely pathogenic/pathogenic (lp/p) SLC6A1 variants and functional data for 184 variants (14.1% lp/p). Clinical and functional data were available for a subset of 126 individuals. We explored the potential associations of variant positions on the GAT1 3D structure with variant pathogenicity, altered molecular function and phenotype severity using bioinformatic approaches.</jats:p> <jats:p>The GAT1 transmembrane domains 1, 6 and extracellular loop 4 (EL4) were enriched for patient over population variants. Across functionally tested missense variants (n = 156), the spatial proximity from the ligand was associated with loss-of-function in the GAT1 transporter activity. For variants with complete loss of in vitro GABA uptake, we found a 4.6-fold enrichment in patients having severe disease versus non-severe disease (P = 2.9 × 10−3, 95% confidence interval: 1.5–15.3).</jats:p> <jats:p>In summary, we delineated associations between the 3D structure and variant pathogenicity, variant function and phenotype in SLC6A1-related disorders. This knowledge supports biology-informed variant interpretation and research on GAT1 function. All our data can be interactively explored in the SLC6A1 portal (https://slc6a1-portal.broadinstitute.org/).</jats:p>
Scopus© Citations 3 3
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Quantitative Phenotype Morbidity Description of SATB2-Associated Syndrome
(2023)
Yuri A. Zarate
;
Katherine Bosanko
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Amrit Kannan
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Ashlen Thomason
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Beth Nutt
<jats:p>Characterized by developmental delay with severe speech delay, dental anomalies, cleft palate, skeletal abnormalities, and behavioral difficulties, SATB2-associated syndrome (SAS) is caused by pathogenic variants in SATB2. The SAS phenotype range of severity has been documented previously in large series. Using data from the SAS registry, we present the SAS severity score, a comprehensive scoring rubric that encompasses 15 different individual neurodevelopmental and systemic features. Higher (more severe) systemic and total (sum of neurodevelopmental and systemic scores) scores were seen for null variants located after amino acid 350 (the start of the CUT1 domain), the recurrent missense Arg389Cys variant (<jats:inline-formula> <math xmlns="http://www.w3.org/1998/Math/MathML" id="M1"> <mi>n</mi> <mo>=</mo> <mn>10</mn> </math> </jats:inline-formula>), intragenic deletions, and larger chromosomal deletions. The Arg389Cys variant had the highest cognitive, verbal, and sialorrhea severity scores, while large chromosomal deletions had the highest expressive, ambulation, palate, feeding and growth, neurodevelopmental, and total scores. Missense variants not located in the CUT1 or CUT2 domain scored lower in several subcategories. We conclude that the SAS severity score allows quantitative phenotype morbidity description that can be used in routine clinical counseling. Further refinement and validation of the SAS severity score are expected over time. All data from this project can be interactively explored in a new portal.</jats:p>
Scopus© Citations 5 7
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Reliability and acceptability of <scp>web‐based</scp> administration of Spanish ages and stages questionnaires third edition®
(2023)
Luisa Schonhaut
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Ivan Armijo
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Paula Rojas B.
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Leonardo Cabrera
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Roberto Boisier
1Scopus© Citations 4 1
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Delineation of functionally essential protein regions for 242 neurodevelopmental genes
(2022)
Sumaiya Iqbal
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Tobias Brünger
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PEREZ PALMA, EDUARDO ESTEBAN
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Marie Macnee
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Andreas Brunklaus
<jats:title>Abstract</jats:title> <jats:p>Neurodevelopmental disorders (NDDs), including severe paediatric epilepsy, autism and intellectual disabilities are heterogeneous conditions in which clinical genetic testing can often identify a pathogenic variant. For many of them, genetic therapies will be tested in this or the coming years in clinical trials. In contrast to first-generation symptomatic treatments, the new disease-modifying precision medicines require a genetic test-informed diagnosis before a patient can be enrolled in a clinical trial. However, even in 2022, most identified genetic variants in NDD genes are ‘variants of uncertain significance’. To safely enrol patients in precision medicine clinical trials, it is important to increase our knowledge about which regions in NDD-associated proteins can ‘tolerate’ missense variants and which ones are ‘essential’ and will cause a NDD when mutated. In addition, knowledge about functionally indispensable regions in the 3D structure context of proteins can also provide insights into the molecular mechanisms of disease variants.</jats:p> <jats:p>We developed a novel consensus approach that overlays evolutionary, and population based genomic scores to identify 3D essential sites (Essential3D) on protein structures. After extensive benchmarking of AlphaFold predicted and experimentally solved protein structures, we generated the currently largest expert curated protein structure set for 242 NDDs and identified 14 377 Essential3D sites across 189 gene disorders associated proteins. We demonstrate that the consensus annotation of Essential3D sites improves prioritization of disease mutations over single annotations. The identified Essential3D sites were enriched for functional features such as intermembrane regions or active sites and discovered key inter-molecule interactions in protein complexes that were otherwise not annotated. Using the currently largest autism, developmental disorders, and epilepsies exome sequencing studies including &gt;360 000 NDD patients and population controls, we found that missense variants at Essential3D sites are 8-fold enriched in patients.</jats:p> <jats:p>In summary, we developed a comprehensive protein structure set for 242 NDDs and identified 14 377 Essential3D sites in these. All data are available at https://es-ndd.broadinstitute.org for interactive visual inspection to enhance variant interpretation and development of mechanistic hypotheses for 242 NDDs genes. The provided resources will enhance clinical variant interpretation and in silico drug target development for NDD-associated genes and encoded proteins.</jats:p>
1Scopus© Citations 6 1
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Comparison between Ages & Stages Questionnaire and Bayley Scales, to predict cognitive delay in school age
(2020)
SCHONHAUT, LUISA
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Marcela Pérez
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Iván Armijo
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MATURANA PEREA, ANDRES
3 1Scopus© Citations 41
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A novel ITPA variant causes epileptic encephalopathy with multiple-organ dysfunction
(2020)
Masamune Sakamoto
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Den Kouhei
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Muzhirah Haniffa
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Sebastián Silva
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Mónica Troncoso
9Scopus© Citations 16
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Clinical, neuroimaging, and molecular spectrum of
<i>TECPR2</i>
‐associated hereditary sensory and autonomic neuropathy with intellectual disability
(2021)
Sonja Neuser
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Barbara Brechmann
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Gali Heimer
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Ines Brösse
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Susanna Schubert
25Scopus© Citations 20
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Reliability and agreement of ages and stages questionnaires®: Results in late preterm and term-born infants at 24 and 48 months
(2019)
SCHONHAUT, LUISA
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Silvia Martinez-Nadal
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Ivan Armijo
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Xavier Demestre
25 1Scopus© Citations 21
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Partial loss-of-function mutations in GINS4 lead to NK cell deficiency with neutropenia
(2022)
Matilde I. Conte
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M. Cecilia Poli
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Angelo Taglialatela
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Giuseppe Leuzzi
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Ivan K. Chinn
9Scopus© Citations 13

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