Cause Of Developmental Delay Research Articles

Performance of second-trimester maternal biochemistry screening (quadruple test vs. triple test) for trisomy 21: An Indian experience.

Background & objectives:Down syndrome (DS) is one of the most common causes of developmental delay. In India, there is no protocol for prenatal screening of DS. Second-trimester biochemical screening is still being done by triple test. Quadruple test is with better sensitivity and specificity but is not advised routinely. So, the objective of this study was to evaluate the sensitivity and accuracy of the second-trimester screening (quadruple test with genetic sonogram) for trisomy 21 as compared to biochemical testing.Methods:This retrospective observational study was carried out in a Fetal Medicine Centre to analyze the odds of being affected with DS, given a positive risk (OAPR) upon screening in the quadruple test; triple test and quadruple test plus a genetic sonogram for high-risk singleton pregnancies (in view of advanced maternal age; an anomaly scan showing some abnormality, etc).Results:3175 high-risk singleton pregnancies were screened for trisomy 21. 394 women underwent amniocentesis on the basis of triple test, quadruple test or quadruple plus genetic sonogram positive. 17 foetuses were diagnosed to have DS. The quadruple test was found to have a higher OAPR as compared to the triple test (1:30.1 as compared to 1: 40.2). Quadruple test plus the genetic sonogram was found to have the highest OAPR of 1:6.Interpretation & conclusions:Best screening for trisomy 21 is provided with quadruple test with genetic sonogram which can lower the rates of unnecessary amniocentesis in high-risk population.

Deep exploration of a CDKN1C mutation causing a mixture of Beckwith-Wiedemann and IMAGe syndromes revealed a novel transcript associated with developmental delay

BackgroundLoss-of-function mutations in CDKN1C cause overgrowth, that is, Beckwith-Wiedemann syndrome (BWS), while gain-of-function variants in the gene’s PCNA binding motif cause a growth-restricted condition called IMAGe syndrome. We report on...

MRI Evaluation of Central Nervous System in Childhood Developmental Delay

Background: Developmental delay is defined as significant delay (more than two standard deviations below the mean) in one or more developmental domains. Developmental delay does not represent a diagnosis, but a term used in different clinical presentations and prognosis, which covers a wide range of etiologies including genetic, metabolic, endocrine, vascular, mal formation syndromes, traumatic, infections, toxins & environmental causes. Careful evaluation and investigation can reveal a cause. Aim of our study to observe efficacy of MRI brain in children with developmental delay and to categories it’s various causes. Subjects and Methods: Record based cross sectional study was done in 200 children, who presented to department of pediatrics with developmental delay and subsequently underwent MRI study.Results:Out of 200 patients 145(72.5%) shows abnormal MRI findings. Most common MRI diagnosis of developmental delay was neurovascular insult (29.5%) followed by structural malformation (21%), infective/inflammatory disorder (17%), metabolic disorders (2.5%) and neoplastic (2.5%). Neurovascular insult was commonly found in 1-5 years of age.Conclusion: MRI is the most useful investigation in patients clinically suspicious for developmental delay and can help in diagnosing the underlying etiology. Other than no of lesions and predominant localization of lesions, encephalomalacia, gliosis, atrophy, structural malformations and neoplastic lesions, ventriculomegaly,micro or megalencephaly are useful features to diagnose underlying cause of developmental delay.

MRI findings in children with global developmental delay

Aim and objective: To determine the prevalence of abnormal brain MRI in children aged 2mon to 12yrs with Global developmental delay. Methods: This is a prospective observational study where a total of 42 children aged 6 month to 12 years with developmental delay who underwent MRI imaging of brain during the study period were included. All patients were evaluated clinically and underwent an MRI of the brain performed using a 1.5 Tesla MRI scanner. MRI scan was done and findings are recorded. Datas were collected and analyzed statistically. Results: Out of 42 children with developmental delay, 52.4% (n=22) were female and 47.6% (n=20) were male children. About 61.9% (n=26) of children with developmental delay had abnormal findings in MRI. All the children with developmental delay have shown abnormal findings in EEG. Among 26 children with abnormal MRI findings, 6 children (23.1%) had hypoxic ischemic changes, 6 children (23.1%) had white matter disorders, 6 children (23.1%) had atropic changes, infection associated changes (n=2), congenital malformations (n=3), two children (7.7%) had CSF disorders and one child (3.8%) had chronic MCA infarct. Conclusion: Though the specific cause of developmental delay often remains unknown, MRI provides useful diagnostic information in a relatively high percentage of children resistant to diagnosis by nonimaging methods.

BAZ2B haploinsufficiency as a cause of developmental delay, intellectual disability, and autism spectrum disorder

The bromodomain adjacent to zinc finger 2B gene (BAZ2B) encodes a protein involved in chromatin remodeling. Loss of BAZ2B function has been postulated to cause neurodevelopmental disorders. To determine whether BAZ2B deficiency is likely to contribute to the pathogenesis of these disorders, we performed bioinformatics analyses that demonstrated a high level of functional convergenceduring fetal cortical developmentbetween BAZ2B and genes known to cause autism spectrum disorder (ASD) and neurodevelopmental disorder. We also found an excess of de novo BAZ2B loss-of-function variants in exome sequencing data from previously published cohorts of individuals with neurodevelopmental disorders. We subsequently identified seven additional individuals with heterozygous deletions, stop-gain, or de novo missense variants affecting BAZ2B. All of these individuals have developmental delay (DD), intellectual disability (ID), and/or ASD. Taken together, our findings suggest that haploinsufficiency of BAZ2B causes a neurodevelopmental disorder, whose cardinal features include DD, ID, and ASD.

Chromosomal Microarray Analysis in Turkish Patients with Unexplained Developmental Delay and Intellectual Developmental Disorders.

Aneuploids, copy number variations (CNVs), and single nucleotide variants in specific genes are the main genetic causes of developmental delay (DD) and intellectual disability disorder (IDD). These genetic changes can be detected using chromosome analysis, chromosomal microarray (CMA), and next-generation DNA sequencing techniques. Therefore; In this study, we aimed to investigate the importance of CMA in determining the genomic etiology of unexplained DD and IDD in 123 patients. For 123 patients, chromosome analysis, DNA fragment analysis and microarray were performed. Conventional G-band karyotype analysis from peripheral blood was performed as part of the initial screening tests. FMR1 gene CGG repeat number and methylation analysis were carried out to exclude fragile X syndrome. CMA analysis was performed in 123 unexplained IDD/DD patients with normal karyotypes and fragile X screening, which were evaluated by conventional cytogenetics. Forty-four CNVs were detected in 39 (39/123=31.7%) patients. Twelve CNV variant of unknown significance (VUS) (9.75%) patients and 7 CNV benign (5.69%) patients were reported. In 6 patients, one or more pathogenic CNVs were determined. Therefore, the diagnostic efficiency of CMA was found to be 31.7% (39/123). Today, genetic analysis is still not part of the routine in the evaluation of IDD patients who present to psychiatry clinics. A genetic diagnosis from CMA can eliminate genetic question marks and thus alter the clinical management of patients. Approximately one-third of the positive CMA findings are clinically intervenable. However, the emergence of CNVs as important risk factors for multiple disorders increases the need for individuals with comorbid neurodevelopmental conditions to be the priority where the CMA test is recommended.

Maternal 2:18 chromosomal translocation manifesting as cause for developmental delay in a proband

Developmental disabilities are a group of related chronic disorders of early onset and said to affect 5% to 10% children. Mental Retardation or intellectual disability has been redefined and replaced with Global developmental delay by WHO as the parameters of diagnosis of such a condition become valid and reliable by the age of five years of the proband. In Indian context the incidence is 2.5%.Chromosomal aberrations either structural or numerical account for 25-30% in general population. Chromosomal analysis and karyotyping is considered as primary investigation in management protocols of such children. Authors present a case of six months old child referred to cytogenetic laboratory with a clinical suspicion of delayed mile stone. Proband was born to a non-consanguineous couple delivered by lower segment caesarian section (LSCS) with no untoward incidents during intraoperative and post-operative phase of surgery. There was history of earlier fetal loss at third month of gestation due to cardiac defects diagnosed prenatally. Karyotyping of proband revealed 2:18 translocation. Karyotype of parents was done to find out the source of translocated chromosome. It was revealed that 2:18 translocated chromosome was seen in karyotype of mother of proband. Karyotype of proband was reported as 46,XX; der(18) t(2:18)(q31q35 ;q21q22)mat As per ISCN guidelines. Case has been reported for the rarity of such an occurrence.

Triac in the treatment of Allan–Herndon–Dudley syndrome

The list of known causes of developmental delay or intellectual disability is growing, with advanced molecular testing now allowing for the identification of the genetic origin of the condition in about 30–40% of patients.1 Developmental delay or intellectual disability occurs in about 3% of the population, and individuals with severe and profound developmental delay typically present within the first 2 years of life, either because of dysmorphic features or notable failure to reach developmental milestones.

TANGO2 deficiency as a cause of neurodevelopmental delay with indirect effects on mitochondrial energy metabolism.

Exome sequencing has recently identified mutations in the gene TANGO2 (transport and Golgi organization 2) as a cause of developmental delay associated with recurrent crises involving rhabdomyolysis, cardiac arrhythmias, and metabolic derangements. The disease is not well understood, in part as the cellular function and subcellular localization of the TANGO2 protein remain unknown. Furthermore, the clinical syndrome with its heterogeneity of symptoms, signs, and laboratory findings is still being defined. Here, we describe 11 new cases of TANGO2-related disease, confirming and further expanding the previously described clinical phenotype. Patients were homozygous or compound heterozygous for previously described exonic deletions or new frameshift, splice site, and missense mutations. All patients showed developmental delay with ataxia, dysarthria, intellectual disability, or signs of spastic diplegia. Of importance, we identify two subjects (aged 12 and 17 years) who have never experienced any overt episode of the catabolism-induced metabolic crises typical for the disease. Mitochondrial complex II activity was mildly reduced in patients investigated in association with crises but normal in other patients. In one deceased patient, post-mortem autopsy revealed heterotopic neurons in the cerebral white matter, indicating a possible role for TANGO2 in neuronal migration. Furthermore, we have addressed the subcellular localization of several alternative isoforms of TANGO2, none of which were mitochondrial but instead appeared to have a primarily cytoplasmic localization. Previously described aberrations in Golgi morphology were not observed in cultured skin fibroblasts.

Vici Syndrome with a Novel Mutation in EPG5

Vici syndrome is a neurodevelopmental disorder of the autophagy pathway. Almost all cases reported have the cardinal features of agenesis of corpus callosum, cataract, cardiomyopathy, immunodeficiency and hypopigmentation. 8-month-old boy with developmental delay, myoclonic jerks, repeated respiratory infections, coarse facial features, cataract and hypopigmented hair. Echocardiography revealed dilated cardiomyopathy and magnetic resonance imaging of brain suggested agenesis of corpus callosum. Exome sequencing detected a novel homozygous nonsense mutation in the EPG5 gene. Establishing a definite diagnosis helped in proper prognostication, providing genetic counseling and prenatal diagnosis to the family. Though uncommon, presence of the characteristic features makes Vici syndrome a clinically recognizable cause of developmental delay.

Vestibular dysfunction is a manifestation of 22q11.2 deletion syndrome.

The 22q11.2 deletion syndrome (22q11.2DS) is the second most common cause of developmental delay after Down syndrome. Impaired cognitive development is highly prevalent, but also motor abnormalities such as hypotonia and delays in achieving motor milestones are described. Instability is frequently detected in children, adolescents, and adults and is mostly attributed to their limited motor performance. Until now, vestibular function has not been investigated in these patients, despite the growing evidence that they often have inner ear malformations. The aim of this prospective study was to identify the presence and character of vestibular dysfunction in 22q11.2DS. We investigated 23 subjects with proven 22q11.2DS, older than the age of 12. We performed caloric testing and pendular rotation chair tests with videonystagmography, cervical vestibular-evoked myogenic potential (c-VEMP)-testing, and posturography. Additional otoscopy and audiometry were performed on all subjects. We found a unilateral caloric hypofunction in 55% of patients, a certain absent c-VEMP response in 15% of ears, an inconclusive c-VEMP response in 33% of ears, and abnormal posturography in 68% of patients, of whom 42% displayed a typical vestibular pattern. Remarkably, 90% revealed uni- or bilateral weak caloric responses, independent of caloric symmetry. Vestibular dysfunction is frequent in subjects with 22q11.2DS. This knowledge should be taken into account when assessing motor performance in these patients. Additional larger studies are needed to determine whether this dysfunction implicates a therapeutic potential.

Prevalence of Congenital Hypothyroidism; in Rural Area of District Gautam Budha Nagar (U.P.)

Introduction:- Congenital hypothyroidism is a condition that affects the newborns and results from a partialor complete loss of thyroid function. Congenital hypothyroidism occurs when the thyroid gland fails todevelop the thyroid hormone or do not function properly. In 80 to 85 percent of cases, the thyroid gland isabsent, abnormally located, or severely reduced in size. In the remaining cases, a normal-sized or enlargedthyroid gland is present, but production of thyroid hormones is decreased or absent. If untreated, congenitalhypothyroidism can lead to intellectual disability and abnormal growth. Iodine is an essential dietary elementwhich is required for the synthesis of the thyroid hormones, thyroxine (T4) and tri-iodothyronine (T3). Inendemic goiter areas, congenital hypothyroidism may occur due to iodine deficiency.Aim:- To screen the Rural area’s neonates for Congenital Hypothyroidism.Results:- The prevalence of CH is 4/161 live birth observed in the rural area of Gautam Buddha NagarDistrict and it also observed that the mean level of TSH was higher in female compared to male neonates.Conclusion:- Despite the overwhelming evidence of a high prevalence of CH in India, this imminentlytreatable cause for developmental delay and mental retardation continues to await a credible universalscreening programme. To get the actual picture of CH in the study area is to need to screen more neonates,which helps to make the more precise evaluation of CH.

Targeted Next-Generation Sequencing of Korean Patients With Developmental Delay and/or Intellectual Disability.

Background: Differential diagnosis of developmental delay (DD) and/or intellectual disability (ID) is challenging because of the diversity of phenotypic manifestations as DD/ID patients usually have combined congenital malformations, autism-spectrum disorders, and/or seizure disorder. Thus, unbiased genomic approaches are needed to discover genetic alterations leading to DD and/or ID.Objective: The aim of this study was to investigate the clinical usefulness of targeted next-generation sequencing (NGS) to investigate genetic causes in 35 Korean patients with unexplained DD/ID.Methods: Targeted next-generation sequencing (NGS) using the TruSight One Panel was analyzed in 35 patients with unexplained DD/ID. Sanger sequencing was used to confirm candidate variants, and to define genetic inheritance mode of candidate variant as familial segregation testing.Results: Of 35 patients with DD and/or ID, 10 were found to have underlying genetic etiology and carried X-linked recessive inheritance of ZDHHC9 or autosomal dominant inheritance of SMARCB1, CHD8, LAMA5, NSD1, PAX6, CACNA1H, MBD5, FOXP1, or KCNK18 mutations. No autosomal recessive inherited mutation was identified in this study. As a result, the diagnostic yield of DD/ID by targeted NGS was 29% (10/35), mostly involving may be de novo mutation present in the proband only. A total of seven may be de novo mutations, one paternally inherited, and one maternally inherited mutations that had been reported previously to concede the genetic pathogenesis as known DD and/or ID genes were found in nine patients with available inheritance pattern except LAMA5. Mutations in nine causative genes were detected in patients with similar DD/ID phenotypes in the OMIM database, providing support for genetic evidence as the cause of DD and/or ID.Conclusion: Targeted NGS through singleton analysis with phenotype-first approaches was able to explain 10 out of 35 DD/ID cases. However, the excavation of plausible genetic causes may be de novo, and X-linked disease-causative variants in DD/ID-associated genes requires further genetic analysis.

De novo mutations in MED13, a component of the Mediator complex, are associated with a novel neurodevelopmental disorder

Many genetic causes of developmental delay and/or intellectual disability (DD/ID) are extremely rare, and robust discovery of these requires both large-scale DNA sequencing and data sharing. Here we describe a GeneMatcher collaboration which led to a cohort of 13 affected individuals harboring protein-altering variants, 11 of which are de novo, in MED13; the only inherited variant was transmitted to an affected child from an affected mother. All patients had intellectual disability and/or developmental delays, including speech delays or disorders. Other features that were reported in two or more patients include autism spectrum disorder, attention deficit hyperactivity disorder, optic nerve abnormalities, Duane anomaly, hypotonia, mild congenital heart abnormalities, and dysmorphisms. Six affected individuals had mutations that are predicted to truncate the MED13 protein, six had missense mutations, and one had an in-frame-deletion of one amino acid. Out of the seven non-truncating mutations, six clustered in two specific locations of the MED13 protein: an N-terminal and C-terminal region. The four N-terminal clustering mutations affect two adjacent amino acids that are known to be involved in MED13 ubiquitination and degradation, p.Thr326 and p.Pro327. MED13 is a component of the CDK8-kinase module that can reversibly bind Mediator, a multi-protein complex that is required for Polymerase II transcription initiation. Mutations in several other genes encoding subunits of Mediator have been previously shown to associate with DD/ID, including MED13L, a paralog of MED13. Thus, our findings add MED13 to the group of CDK8-kinase module-associated disease genes.

Ocular manifestations of PACS1 mutation

Heterozygous mutation in the PACS1 (phosphofurin acidic cluster sorting proteins 1) gene is a known cause of developmental delay, multiple congenital anomalies, dysmorphism, and ocular abnormalities. We present the case of an affected 10-year-old girl, conceived by assisted reproductive technology, who has ocular coloboma and findings characteristic of PACS1 mutation.

Etiological Profile of Children with Global Developmental Delay: A Single Center Study

AbstractGlobal developmental delay (GDD) is a relatively common pediatric issue. It can have plethora of causes. Early intervention in these children by finding the cause of developmental delay is often challenging but can definitely improve ultimate developmental outcome. The study was undertaken to study the clinical profile of children with GDD to assess the etiology of delay in these children. The study was performed in the Department of Pediatrics, SMS Medical College, Jaipur, from June 2014 to May 2015. One hundred sixty-eight children with GDD attending the child development clinic with age ≤ 5 years and development quotient < 70% were enrolled. After detailed clinical history and thorough examination, specific investigations were obtained. Data analysis was done to determine the underlying etiology. Out of 168 children studied, etiology was detected in 155 (92.3%). Most common etiology was perinatal insult (63.1%) followed by genetic (8.93%), postnatal (7.14%), metabolic (5.95%), mixed (2.98%), cerebral dysgenesis (2.38%), and congenital infections (1.79%). Microcephaly was present in 100 children. Most common etiology was found to be perinatal insult, which is a preventable cause to much extent. Newer and sophisticated investigations such as metabolic profile, genetic studies should be incorporated in the planned investigations to increase the diagnostic yield.

Phenotypic spectrum associated with de novo mutations in QRICH1 gene.

Rare de novo mutations represent a significant cause of idiopathic developmental delay (DD). The use of next-generation sequencing (NGS) has boosted the identification of de novo mutations in an increasing number of novel genes. Here we present 3 unrelated children with de novo loss-of-function (LoF) mutations in QRICH1, diagnosed through trio-based exome sequencing. QRICH1 encodes the glutamine-rich protein 1, which contains 1 caspase activation recruitment domain and is likely to be involved in apoptosis and inflammation. All 3 children had speech delay, learning difficulties, a prominent nose and a thin upper lip. In addition, 2 of them had mildly raised creatine kinase (CK) and 1 of them had autism. Despite their small number, the patients had a relatively consistent pattern of clinical features suggesting the presence of a QRICH1-associated phenotype. LoF mutations in QRICH1 are suggested as a novel cause of DD.

On the Cause and Mechanism of Phenoptosis.

Based upon evolvability theory, phenotypes like aging that offer no apparent individual benefit may evolve nonetheless. Pursuant to that concept, the evolution of a hypothetical, genome-based aging program called phenoptosis was proposed. However, while aging may facilitate evolvability, it need not result from a program specifically selected for that purpose. Instead, it is possible that the potential for aging is conserved within the genome as a part of a beneficial program that orchestrates and integrates developmental transformation of the soma from conception to maturation. Because somatic remodeling is inherently unstable, its continued non-programmatic expression beyond young adulthood (developmental inertia) erodes internal order, initiating and exacerbating aging. Thus, aging may result paradoxically from post-maturational expression of the same programmatic function for somatic transformation that previously provided individual benefit. It did so by ensuring acquisition of reproductive competence, post-reproductive development of parents to nurture offspring and thereby, to guarantee species survival. In an attempt to identify genes capable of controlling developmental inertia, we sequenced DNA from a series of subjects displaying extreme neoteny, i.e. retention of youthful characteristics during adulthood. We hoped to identify mutations associated with delayed development and to compare each subject's biological and chronological ages. De novo mutations of coding-genes were found in all the subjects, but they could not be definitively identified as a cause of developmental delay. Nonetheless, genetic and epigenetic studies of neotenic subject's DNA are on-going. We are attempting to determine if phenoptosis specifically evolved to cause aging, or rather if it exists as a cryptic component of the developmental program that expresses its lethal potential serendipitously and only after individual benefit is realized.

A rare cause of developmental delay and epilepsy in two siblings: Asparagine synthetase deficiency

Objective: Asparagine synthetase deficiency (ASNSD) is a recently described neurometabolic disorder characterized by congenital microcephaly, global developmental delay and variable seizures. Diagnosis is confirmed by findings of low cerebral spinal fluid or plasma asparagine in addition to a mutation in the ASNS gene. Case presentation: We report two siblings at the age of 18 months and 3 years, both presented with global developmental delay, epilepsy, microcephaly, axial hypotonia and lower limb spasticity. Brain magnetic resonance imaging showed marked cerebral atrophy. Numerous metabolic tests including plasma and cerebro-spinal fluid (CSF) amino acid profile did not lead to diagnosis. We identified a novel homozygous missense mutation in the ASNS gene, on position c.1108 C>T (p. Leu370Phe) in both siblings by whole exome sequencing (WES). Conclusion: ASNS deficiency is a very rare disorder; there are a few reported patients in the literature. ASNS deficiency should be kept in mind in any newborn presented with severe congenital microcephaly followed by severe epilepsy and global developmental delay. Plasma or asparagine levels may be nonspecific as in our patient. We would like to highlight the role of WES in the diagnosis of a condition with potential therapeutic option. Our patients showed some improvement in the seizure frequency and motor functions after the administration of asparagine supplementation.

Language ENvironment Analysis (LENA) in Phelan-McDermid Syndrome: Validity and Suggestions for Use in Minimally Verbal Children with Autism Spectrum Disorder.

Phelan-McDermid syndrome (PMS) is a single-locus cause of developmental delay, autism spectrum disorder, and minimal verbal abilities. There is an urgent need to identify objective outcome measures of expressive language for use in this and other minimally verbal populations. One potential tool is an automated language processor called Language ENvironment Analysis (LENA). LENA was used to obtain over 542h of audio in 18 children with PMS. LENA performance was adequate in a subset of children with PMS, specifically younger children and those with fewer stereotypic vocalizations. One LENA-derived language measure, Vocalization Ratio, had improved accuracy in this sample and may represent a novel expressive language measure for use in severely affected populations.