scholarly journals Clinical and Genetic Characteristics and Prenatal Diagnosis of Rare Monogenic Global Developmental Delay and Intellectual Disability.

2020 ◽  
Author(s):  
Liling Lin ◽  
Ying Zhang ◽  
Hong Pan ◽  
Jingmin Wang ◽  
Yu Qi ◽  
...  
Keyword(s):  
Intellectual Disability ◽  
Prenatal Diagnosis ◽  
Developmental Delay ◽  
Hot Spot ◽  
Disease Onset ◽  
Genetic Diagnosis ◽  
Global Developmental Delay ◽  
Genetic Characteristics ◽  
Pathogenic Variants

Abstract Background: The estimated worldwide prevalence of global developmental delay (GDD) and intellectual disability (ID) is 1-3%. Rare monogenic GDD/ID is poorly characterized because its low prevalence limits research. In this study, we aimed to describe the diagnostic courses and clinical and genetic characteristics of a cohort with rare monogenic GDD/ID.Method:We retrospectively analyzed the diagnostic courses, clinical characteristics, and genetic spectra of rare monogenic GDD/ID patients. We also conducted a follow-up study on prenatal diagnosis in these families. Mutation pathogenicity was interpreted by molecular geneticists and clinicians according to the guidelines of the American College of Medical Genetics and Genomics. Results:Among 108 patients with rare monogenic GDD/ID, it often took 0.5-4 years and 3-5 referrals to obtain a genetic diagnosis after disease onset. Onset typically occurred before 6 years of age, and patients usually presented moderate to severe GDD/ID. The most common coexisting conditions were epilepsy (68%), facial dysmorphism (14%) and microcephaly (13%). In total, 149 different pathogenic variants were found in 81 different genes among the 108 pedigrees, and 71 variants were novel. The most common inheritance patterns in this outbred Chinese population were autosomal recessive (AR; 46.3%), autosomal dominant (AD; 37%), and X-linked (XL; 16.7%). GLB1, PLA2G6, SCN2A, SHANK3 and STXBP1 were important causal genes. Hot-spot mutations were rarely found. By the follow-up, 43 families, including 24 ARID, 13 ADID and 6 XLID families, had undergone prenatal diagnosis. The offspring of 6 ARID, 2 ADID and 2 XLID families had the same pathogenic variants as the probands.Conclusion:Rare monogenic GDD/ID is characterized by early onset, relatively severe symptoms, great clinical variability and genetic heterogeneity. Moreover, timely referrals to genetic counseling and prenatal diagnostic laboratories are important for affected families planning to have additional children.

scholarly journals Clinical and genetic characteristics and prenatal diagnosis of patients presented GDD/ID with rare monogenic causes

2020 ◽  
Author(s):  
Liling Lin ◽  
Ying Zhang ◽  
Hong Pan ◽  
Jingmin Wang ◽  
Yu Qi ◽  
...  
Keyword(s):  
Genetic Counseling ◽  
Prenatal Diagnosis ◽  
Hot Spot ◽  
Single Gene ◽  
Global Developmental Delay ◽  
Recurrence Rates ◽  
Genetic Characteristics ◽  
Prenatal Diagnostic ◽  
Diagnostic Center

Abstract Background: Global developmental delay/intellectual disability (GDD/ID), used to be named as mental retardation (MR), is one of the most common phenotypes in neurogenetic diseases. In this study, we described the diagnostic courses, clinical and genetic characteristics and prenatal diagnosis of a cohort with patients presented GDD/ID with monogenic causes, from the perspective of a tertiary genetic counseling and prenatal diagnostic center.Method:We retrospectively analyzed the diagnostic courses, clinical characteristics, and genetic spectrum of patients presented GDD/ID with rare monogenic causes. We also conducted a follow-up study on prenatal diagnosis in these families. Pathogenicity of variants was interpreted by molecular geneticists and clinicians according to the guidelines of the American College of Medical Genetics and Genomics (ACMG).Results:Among 81 [1] patients with GDD/ID caused by rare monogenic variants it often took 0.5-4.5 years and 2-8 referrals to obtain genetic diagnoses. Devlopmental delay typically occurred before 3 years of age, and patients usually presented severe to profound GDD/ID. The most common co-existing conditions were epilepsy (58%), microcephaly (21%) and facial anomalies (17%). In total, 111 pathogenic variants were found in 62 different genes among the 81 pedigrees, and 56 variants were novel. The most common inheritance patterns in this outbred Chinese population were autosomal dominant (AD; 47%), following autosomal recessive (AR; 37%), and X-linked (XL; 16%). SCN2A, SHANK3 and STXBP1 were important causal genes. Hot-spot variants were rarely found. By the follow-up, 33 affected families, including 15, 13 and 5 families inherited in AR, AD and XL modes respectively, had undergone prenatal diagnosis. And the recurrence rates are 26.7%, 15.4% and 20% for families inherited in AR, AD, and XL patterns.Conclusion:Patients presented with GDD/ID caused by rare single gene variants are characterized by early onset, relatively severe symptoms and great clinical variability and genetic heterogeneity. Timely referrals to genetic counseling and prenatal diagnostic laboratories are important for affected families planning to have additional children.

scholarly journals Clinical and genetic characteristics and prenatal diagnosis of patients presented GDD/ID with rare monogenic causes

2020 ◽  
Vol 15 (1) ◽  
Author(s):  
Liling Lin ◽  
Ying Zhang ◽  
Hong Pan ◽  
Jingmin Wang ◽  
Yu Qi ◽  
...  
Keyword(s):  
Genetic Counseling ◽  
Prenatal Diagnosis ◽  
Hot Spot ◽  
Single Gene ◽  
Global Developmental Delay ◽  
Recurrence Rates ◽  
Genetic Characteristics ◽  
Prenatal Diagnostic ◽  
Diagnostic Center

Abstract Background Global developmental delay/intellectual disability (GDD/ID), used to be named as mental retardation (MR), is one of the most common phenotypes in neurogenetic diseases. In this study, we described the diagnostic courses, clinical and genetic characteristics and prenatal diagnosis of a cohort with patients presented GDD/ID with monogenic causes, from the perspective of a tertiary genetic counseling and prenatal diagnostic center. Method We retrospectively analyzed the diagnostic courses, clinical characteristics, and genetic spectrum of patients presented GDD/ID with rare monogenic causes. We also conducted a follow-up study on prenatal diagnosis in these families. Pathogenicity of variants was interpreted by molecular geneticists and clinicians according to the guidelines of the American College of Medical Genetics and Genomics (ACMG). Results Among 81 patients with GDD/ID caused by rare monogenic variants it often took 0.5–4.5 years and 2–8 referrals to obtain genetic diagnoses. Devlopmental delay typically occurred before 3 years of age, and patients usually presented severe to profound GDD/ID. The most common co-existing conditions were epilepsy (58%), microcephaly (21%) and facial anomalies (17%). In total, 111 pathogenic variants were found in 62 different genes among the 81 pedigrees, and 56 variants were novel. The most common inheritance patterns in this outbred Chinese population were autosomal dominant (AD; 47%), following autosomal recessive (AR; 37%), and X-linked (XL; 16%). SCN2A, SHANK3 and STXBP1 were important causal genes. Hot-spot variants were rarely found. By the follow-up, 33 affected families, including 15, 13 and 5 families inherited in AR, AD and XL modes respectively, had undergone prenatal diagnosis. And the recurrence rates are 26.7%, 15.4% and 20% for families inherited in AR, AD, and XL patterns. Conclusion Patients presented with GDD/ID caused by rare single gene variants are characterized by early onset, relatively severe symptoms and great clinical variability and genetic heterogeneity. Timely referrals to genetic counseling and prenatal diagnostic laboratories are important for affected families planning to have additional children.

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

2012 ◽  
Vol 03 (03) ◽  
pp. 244-250 ◽  
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.

scholarly journals De novo pathogenic variants inCHAMP1are associated with global developmental delay, intellectual disability, and dysmorphic facial features

2015 ◽  
Vol 2 (1) ◽  
pp. a000661 ◽  
Author(s):  
Akemi J. Tanaka ◽  
Megan T. Cho ◽  
Kyle Retterer ◽  
Julie R. Jones ◽  
Catherine Nowak ◽  
...  
Keyword(s):  
Intellectual Disability ◽  
Developmental Delay ◽  
De Novo ◽  
Global Developmental Delay ◽  
Facial Features ◽  
Pathogenic Variants

scholarly journals Shukla-Vernon Syndrome: A Second Family with a Novel Variant in the BCORL1 Gene

Genes ◽  
2021 ◽  
Vol 12 (3) ◽  
pp. 452
Author(s):  
Babylakshmi Muthusamy ◽  
Anikha Bellad ◽  
Satish Chandra Girimaji ◽  
Akhilesh Pandey
Keyword(s):  
Intellectual Disability ◽  
Developmental Delay ◽  
Protein Complexes ◽  
Neurodevelopmental Disorder ◽  
Missense Variant ◽  
Global Developmental Delay ◽  
Dysmorphic Features ◽  
Pathogenic Variants ◽  
Behavioral Abnormalities ◽  
Novel Variant

Shukla-Vernon syndrome (SHUVER) is an extremely rare neurodevelopmental disorder characterized by global developmental delay, intellectual disability, behavioral anomalies, and dysmorphic features. Pathogenic variants in the BCORL1 gene have been identified as the molecular cause for this disorder. The BCORL1 gene encodes for BCL-6 corepressor-like protein 1, a transcriptional corepressor that is an integral component of protein complexes involved in transcription repression. In this study, we report an Indian family with two male siblings with features of Shukla-Vernon syndrome. The patients exhibited global developmental delay, intellectual disability, kyphosis, seizures, and dysmorphic features including bushy prominent eyebrows with synophrys, sharp beaked prominent nose, protuberant lower jaw, squint, and hypoplastic ears with fused ear lobes. No behavioral abnormalities were observed. Whole exome sequencing revealed a novel potentially pathogenic arginine to cysteine substitution (p.Arg1265Cys) in the BCORL1 protein. This is the second report of Shukla-Vernon syndrome with a novel missense variant in the BCORL1 gene. Our study confirms and expands the phenotypes and genotypes described previously for this syndrome and should aid in diagnosis and genetic counselling of patients and their families.

Complications and Sequelae in Patients With Congenital Microcephaly Associated With Zika Virus Infection: Two-Year Follow-Up

2021 ◽  
pp. 088307382098316
Author(s):  
Luane A. Gouvea ◽  
Marlos Martins ◽  
Daniela Vivacqua ◽  
Julia Rosseto ◽  
Giulia Lima ◽  
...  
Keyword(s):  
Developmental Delay ◽  
Zika Virus ◽  
Median Number ◽  
Global Developmental Delay ◽  
Spastic Diplegia ◽  
Long Term Follow Up ◽  
Congenital Microcephaly ◽  
Auditory Impairment ◽  
Worse Prognosis

Background: We aim to describe the long term follow-up of a cohort of children exposed in utero to the Zika virus. Methods: Descriptive study of a cohort of microcephalic children due to Zika virus. Logistic regression was used to evaluate variables associated with worse prognosis epilepsy. Results: We followed 28 children (15 females), with a median follow-up of 24 months (IQR = 12-28). During the follow-up, 1 infant died. The median head circumference at birth was 29 cm (IQR = 27-31). All presented a global developmental delay. The most frequent central nervous system abnormalities were on cortical development in 22 participants; dysgenesis of corpus callosum in 13; ventriculomegaly in 25; and calcifications in 24. A total of 9 presented ocular abnormalities, 4 auditory impairment. During follow-up, 12 presented with sleep disorders, 10 with irritability, and 23 with epilepsy (2 with generalized tonic-clonic, 3 with generalized tonic-clonic and spasms, 12 with spasms, 3 tonic and spasms, and 3 motor focal and spasms). The median age at the begin of the epilepsy was 4 months (IQR = 2-10), the median number of drugs used to control the epilepsy was 2 (IQR = 2-3). Maternal illicit drug use during pregnancy was associated with worse prognosis epilepsy (Lennox-Gastaut syndrome, West syndrome, or status epilepticus). A total of 19 presented with dysphagia, 10 children required gastrostomy. Conclusion: Children with microcephaly due to Zika virus presented with several complications during follow-up, as epilepsy, spastic diplegia, and global developmental delay.

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

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

scholarly journals Phenotypes in Children With SYNGAP1 Encephalopathy in China

2021 ◽  
Vol 15 ◽  
Author(s):  
Huiting Zhang ◽  
Liu Yang ◽  
Jing Duan ◽  
Qi Zeng ◽  
Li Chen ◽  
...  
Keyword(s):  
Developmental Delay ◽  
Behavioral Problems ◽  
Disease Onset ◽  
Gene Mutations ◽  
Global Developmental Delay ◽  
Clinical Trial Registry ◽  
Neurodevelopmental Delay ◽  
Epileptic Spasms ◽  
Registration Number ◽  
Drug Resistant Epilepsy

Objective: We aimed to explore the associated clinical phenotype and the natural history of patients with SYNGAP1 gene variations during early childhood and to identify their genotype–phenotype correlations.Methods: This study used a cohort of 13 patients with epilepsy and developmental disorder due to SYNGAP1 mutations, namely, 7 patients from Shenzhen Children’s Hospital between September 2014 and January 2020 and 6 patients from previously published studies. Their clinical data were studied.Results: A total of 13 children with SYNGAP1 gene variants (eight boys and five girls) were identified. The age of disease onset was in infancy. Mutations were located between exons 8 and 15; most were frameshift or truncated mutations. Four mutation sites (c.924G &gt; A, c.1532-2_1532del, c.1747_1755dup, and c.1735_1738del) had not been reported before. All patients had global developmental delay within the first year of life, and intellectual impairment became gradually apparent. Some of them developed behavioral problems. The developmental delay occurred before the onset of seizures. All seven patients in our cohort presented with epilepsy; myoclonic seizures, absence seizures, and epileptic spasms were the most common seizure types. Abnormal electroencephalograms were identified from five patients before the onset of their seizures. All patients suffered from drug-resistance seizures. However, comorbidities such as behavioral problems were less frequently observed.Conclusion: The most common age of disease onset in SYNGAP1 gene mutations is in infancy, while neurodevelopmental delay and epilepsy are the major phenotypes. They have a higher percentage of drug-resistant epilepsy and epileptic spasms than those in previous reports. We should give attention to the patients with abnormal EEGs without seizures and think about the suitable time of the anti-seizure medications for them. We have not found the genotype–phenotype correlation.Trial registration: Chinese Clinical Trial Registry, Registration number: ChiCTR2100049289 (https://www.chictr.org.cn/listbycreater.aspx).

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