Diagnostic yield from routine metabolic screening tests in evaluation of global developmental delay and intellectual disability

Abstract Global developmental delay and intellectual disability (GDD/ID) affect 3% of the paediatric population. Although inborn errors of metabolism (IEM) are not a common cause of GDD/ID, early therapeutic intervention can improve neurodevelopmental manifestations. In 2012, a first-tier test panel, including specialized metabolic and routine chemistry tests, was piloted to community-based paediatricians in British Columbia with aims to achieve earlier diagnosis of treatable IEM. Objective The aim of this retrospective review was to evaluate the diagnostic yield from these first-tier tests in the 7 years before (2006 to 2012) and after (2013 to 2019) implementation at the community paediatrician level. Results Prior and postimplementation diagnostic yield of an IEM from first-tier metabolic testing was 9 out of 986 (0.91%) and 11 out of 4,345 children (0.25%), respectively. Disorders of creatine metabolism and organic acidurias were the most frequently established diagnoses in both time periods. No diagnoses were established through acylcarnitine copper/ceruloplasmin, lactate, or ammonia testing. Twenty out of 24 patients had specific neurological or other red flag signs in addition to GDD/ID. Four boys diagnosed with an x-linked creatine transporter defect (CTD) had speech-language delay as the most prominent finding. Conclusions The expansion of first-tier metabolic testing to community-based paediatricians in BC did not yield an increase in IEM diagnoses. A modified first-tier test panel should be offered to patients with GDD/ID, neurologic, and/or red flag signs. Urine creatine testing in boys with speech-language delay warrants consideration to detect CTD.

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Next-generation sequencing is a powerful method to enhance diagnostic yield in global developmental delay/intellectual disability

Clinical and Experimental Pediatrics ◽

10.3345/cep.2019.01683 ◽

2020 ◽

Vol 63 (6) ◽

pp. 211-212 ◽

Cited By ~ 1

Author(s):

Jon Soo Kim

Keyword(s):

Intellectual Disability ◽

Next Generation Sequencing ◽

Developmental Delay ◽

Diagnostic Yield ◽

Global Developmental Delay ◽

Powerful Method ◽

Next Generation ◽

Generation Sequencing

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Delineating the molecular and phenotypic spectrum of the SETD1B-related syndrome

Genetics in Medicine ◽

10.1038/s41436-021-01246-2 ◽

2021 ◽

Author(s):

Marjolein J. A. Weerts ◽

Kristina Lanko ◽

Francisco J. Guzmán-Vega ◽

Adam Jackson ◽

Reshmi Ramakrishnan ◽

...

Keyword(s):

Intellectual Disability ◽

Developmental Delay ◽

Neurodevelopmental Disorder ◽

Epileptic Activity ◽

Language Delay ◽

Global Developmental Delay ◽

Sequence Variants ◽

Loss Of Function ◽

Phenotypic Spectrum

Abstract Purpose Pathogenic variants in SETD1B have been associated with a syndromic neurodevelopmental disorder including intellectual disability, language delay, and seizures. To date, clinical features have been described for 11 patients with (likely) pathogenic SETD1B sequence variants. This study aims to further delineate the spectrum of the SETD1B-related syndrome based on characterizing an expanded patient cohort. Methods We perform an in-depth clinical characterization of a cohort of 36 unpublished individuals with SETD1B sequence variants, describing their molecular and phenotypic spectrum. Selected variants were functionally tested using in vitro and genome-wide methylation assays. Results Our data present evidence for a loss-of-function mechanism of SETD1B variants, resulting in a core clinical phenotype of global developmental delay, language delay including regression, intellectual disability, autism and other behavioral issues, and variable epilepsy phenotypes. Developmental delay appeared to precede seizure onset, suggesting SETD1B dysfunction impacts physiological neurodevelopment even in the absence of epileptic activity. Males are significantly overrepresented and more severely affected, and we speculate that sex-linked traits could affect susceptibility to penetrance and the clinical spectrum of SETD1B variants. Conclusion Insights from this extensive cohort will facilitate the counseling regarding the molecular and phenotypic landscape of newly diagnosed patients with the SETD1B-related syndrome.

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Genome sequencing demonstrates high diagnostic yield in children with undiagnosed global developmental delay/intellectual disability: a prospective study

10.22541/au.163253634.46825323/v1 ◽

2021 ◽

Author(s):

Yu Sun ◽

Jing Peng ◽

Desheng Liang ◽

Xiantao Ye ◽

Na Xu ◽

...

Keyword(s):

Intellectual Disability ◽

Developmental Delay ◽

Genome Sequencing ◽

Clinical Utility ◽

Diagnostic Yield ◽

Chromosomal Microarray ◽

Global Developmental Delay ◽

Chromosomal Microarray Analysis ◽

High Diagnostic Yield ◽

Wide Range

Genome sequencing(GS) has been applied in the diagnosis of global developmental delay(GDD)/intellectual disability(ID). However, the performance in those with inconclusive results from chromosomal microarray analysis(CMA) and exome sequencing(ES) is unknown. We recruited 100 pediatric GDD/ID patients from multiple sites in China from February 2018 to August 2020 for GS. Patients have received at least one genomic diagnostic test prior to enrollment. Reanalysis of CMA/ES data was performed. The yield of GS was calculated and explanations for missed diagnoses by CMA/ES were investigated. Clinical utility was assessed by interviewing the parents by phone. The overall diagnostic yield of GS was 23%. Seven families could have been solved with reanalysis of ES data. 13 families were missed by previous CMA/ES due to improper method. Three remained unsolved after ES reanalysis due to allele dropout, complex variants missed by ES, and a CNV in untranslated regions. Follow-up of the diagnosed families revealed that nine families experienced changes in clinical management, including identification of targeted treatments, cessation of unnecessary treatment, and considerations for family planning. GS demonstrated high diagnostic yield and clinical utility in this cohort of undiagnosed GDD/ID patients, detecting a wide range of variant types of different sizes in a single workflow.

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Diagnostic and Clinical Utility of Clinical Exome Sequencing in Children With Moderate and Severe Global Developmental Delay / Intellectual Disability

Journal of Child Neurology ◽

10.1177/0883073819879835 ◽

2019 ◽

Vol 35 (2) ◽

pp. 116-131 ◽

Cited By ~ 3

Author(s):

Jelena Ruml Stojanovic ◽

Aleksandra Miletic ◽

Borut Peterlin ◽

Ales Maver ◽

Marija Mijovic ◽

...

Keyword(s):

Intellectual Disability ◽

Exome Sequencing ◽

Developmental Delay ◽

Clinical Utility ◽

Diagnostic Yield ◽

Genetic Disorders ◽

Significant Proportion ◽

Global Developmental Delay ◽

Clinical Exome Sequencing ◽

The Impact

Clinical exome sequencing is currently being used in diagnostics of various genetic disorders, but studies supporting its application in clinical setting are scarce. The aim of this study was to establish diagnostic and clinical utility of clinical exome sequencing in patients with moderate and severe global developmental delay/intellectual disability. Clinical diagnosis was made in 49 of 88 investigated patients, with overall diagnostic yield of 55.7%. Molecular findings are characterized in detail, including the impact of newly made diagnosis on clinical management. Several previously unreported genotype-phenotype correlations and 33 novel variants are described. Genetic and clinical data were shared through publicly available database. In conclusion, clinical exome sequencing allows identification of causative variants in a significant proportion of patients in investigated clinical subgroup. Compared to whole exome sequencing, it shows similar diagnostic and clinical utility with reduced costs, which could be of particular importance for institutions with limited resources.

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Delineating the molecular and phenotypic spectrum of the SETD1B-related syndrome

10.1101/2021.02.11.430742 ◽

2021 ◽

Author(s):

Marjolein J.A. Weerts ◽

Kristina Lanko ◽

Francisco J. Guzmán-Vega ◽

Adam Jackson ◽

Reshmi Ramakrishnan ◽

...

Keyword(s):

Intellectual Disability ◽

Developmental Delay ◽

Neurodevelopmental Disorder ◽

Epileptic Activity ◽

Language Delay ◽

Global Developmental Delay ◽

Sequence Variants ◽

Loss Of Function ◽

Phenotypic Spectrum

ABSTRACTPathogenic variants in SETD1B have been associated with a syndromic neurodevelopmental disorder including intellectual disability, language delay and seizures. To date, clinical features have been described for eleven patients with (likely) pathogenic SETD1B sequence variants. We perform an in-depth clinical characterization of a cohort of 36 unpublished individuals with SETD1B sequence variants, describing their molecular and phenotypic spectrum. Selected variants were functionally tested using in vitro and genome-wide methylation assays. Our data present evidence for a loss-of-function mechanism of SETD1B variants, resulting in a core clinical phenotype of global developmental delay, language delay including regression, intellectual disability, autism and other behavioral issues, and variable epilepsy phenotypes. Developmental delay appeared to precede seizure onset, suggesting SETD1B dysfunction impacts physiological neurodevelopment even in the absence of epileptic activity. Interestingly, males are significantly overrepresented and more severely affected, and we speculate that sex-linked traits could affect susceptibility to penetrance and the clinical spectrum of SETD1B variants. Finally, despite the possibility of non-redundant contributions of SETD1B and its paralogue SETD1A to epigenetic control, the clinical phenotypes of the related disorders share many similarities, indicating that elucidating shared and divergent downstream targets of both genes will help to understand the mechanism leading to the neurobehavioral phenotypes. Insights from this extensive cohort will facilitate the counseling regarding the molecular and phenotypic landscape of newly diagnosed patients with the SETD1B-related syndrome.

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Biallelic UBE4A loss-of-function variants cause intellectual disability and global developmental delay

Genetics in Medicine ◽

10.1038/s41436-020-01047-z ◽

2021 ◽

Author(s):

Uirá Souto Melo ◽

Devon Bonner ◽

Kevin C. Kent Lloyd ◽

Ala Moshiri ◽

Brandon Willis ◽

...

Keyword(s):

Intellectual Disability ◽

Developmental Delay ◽

Global Developmental Delay ◽

Loss Of Function

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Characteristics of seizure frequency among Malaysian children diagnosed with structural– metabolic epilepsy

Journal of Neurosciences in Rural Practice ◽

10.4103/0976-3147.102596 ◽

2012 ◽

Vol 03 (03) ◽

pp. 244-250 ◽

Cited By ~ 1

Author(s):

Muhannad RM Salih ◽

Mohd Baidi Bahari ◽

Mohamed Azmi Ahmad Hassali ◽

Asrul Akmal Shafie ◽

Omer Qutaiba B Al-lela ◽

...

Keyword(s):

Intellectual Disability ◽

Developmental Delay ◽

Seizure Frequency ◽

Substantial Reduction ◽

Focal Seizure ◽

Global Developmental Delay ◽

Neurology Clinic ◽

Collection Form ◽

Metabolic Epilepsy

ABSTRACT Introduction: Seizure-free patients or substantial reduction in seizure frequency are the most important outcome measures in the management of epilepsy. The study aimed to evaluate the patterns of seizure frequency and its relationship with demographics, clinical characteristics, and outcomes. Materials and Methods: A retrospective cohort study was conducted at the Pediatric Neurology Clinic, Hospital Pulau Pinang. Over a period of 6 months, the required data were extracted from the medical records using a pre-designed data collection form. Results: Seizure frequency showed no significant association with patient’s demographics and clinical characteristic. However, significant reduction in seizure frequency from the baseline to the last follow-up visit was only seen in certain subgroups of patients including Malays, females, patients <4 years of age, patients with global developmental delay/intellectual disability, and patients with focal seizure. There was no significant association between seizure frequency and rate of adverse events. Polytherapy visits were associated with higher seizure frequency than monotherapy visits (27.97 ± 56.66, 10.94 ± 30.96 attack per month, respectively) (P < 0.001). There was a clear tendency to get antiepileptic drugs used at doses above the recommended range in polytherapy (8.4%) rather than in monotherapy (1.4%) visits (P < 0.001). A significant correlation was found between seizure frequency and number of visits per patient per year (r = 0.450, P < 0.001). Conclusion: Among children with structural–metabolic epilepsy, Malays, females, patients <4 years of age, patients with global developmental delay/intellectual disability and patients manifested with focal seizure are more responsive antiepileptic drug therapy than the other subgroups of patients.

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