Abstract
BackgroundDue to extensive clinical and genetic heterogeneity of intellectual disability (ID) syndromes, the process of diagnosis is very challenging even for expert clinicians. Despite recent advancements in molecular diagnostics methodologies, a significant fraction of ID patients remains without a clinical diagnosis.Methods, results, and conclusionsHere, in a prospective study on a cohort of 21 families (trios) with a child presenting with ID of unknown etiology, we executed phenotype‐driven bioinformatic analysis method, PhenIX, utilizing targeted next‐generation sequencing (NGS) data and Human Phenotype Ontology (HPO)‐encoded phenotype data. This approach resulted in clinical diagnosis for eight individuals presenting with atypical manifestations of Rubinstein–Taybi syndrome 2 (MIM 613684), Spastic Paraplegia 50 (MIM 612936), Wiedemann–Steiner syndrome (MIM 605130), Cornelia de Lange syndrome 2 (MIM 300590), Cerebral creatine deficiency syndrome 1 (MIM 300352), Glass Syndrome (MIM 612313), Mental retardation, autosomal dominant 31 (MIM 616158), and Bosch–Boonstra–Schaaf optic atrophy syndrome (MIM 615722).
Highlights
Intellectual disability (ID) patients and their families often experience diagnostic odyssey
The introduction of next-generation sequencing (NGS) has revolutionized diagnostics for intellectual disability patients (Gilissen et al, 2014; Najmabadi et al, 2011). Another significant recent methodological advancement has been the implementation of Human Phenotype Ontology (HPO) (Kohler et al, 2017), providing standardized vocabulary allowing for the description of patient phenotypes
By applying Phenotypic Interpretation of eXomes (PhenIX) bioinformatic method to nextgeneration sequencing (NGS) and phenotypic data of 21 examined intellectual disability (ID) patients, the etiological diagnosis was made in eight cases
Summary
Intellectual disability (ID) patients and their families often experience diagnostic odyssey. Results, and conclusions: Here, in a prospective study on a cohort of 21 families (trios) with a child presenting with ID of unknown etiology, we executed phenotype-driven bioinformatic analysis method, PhenIX, utilizing targeted nextgeneration sequencing (NGS) data and Human Phenotype Ontology (HPO)-encoded phenotype data This approach resulted in clinical diagnosis for eight individuals presenting with atypical manifestations of Rubinstein–Taybi syndrome 2 (MIM 613684), Spastic Paraplegia 50 (MIM 612936), Wiedemann–Steiner syndrome (MIM 605130), Cornelia de Lange syndrome 2 (MIM 300590), Cerebral creatine deficiency syndrome 1 (MIM 300352), Glass Syndrome (MIM 612313), Mental retardation, autosomal dominant 31 (MIM 616158), and Bosch–Boonstra–Schaaf optic atrophy syndrome (MIM 615722). AP4M1, dysmorphology, EP300, HPO, intellectual disability patients, KMT2A, NR2F1, PhenIX, Phenomizer, PURA, SATB2, SLC6A8, SMC1A
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