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Global developmental delay – Genetics and genetic testing 

Global developmental delay and intellectual disability (GDD/ID) affect up to 3% of children <5 years old and is defined as a delay in ≥2 developmental domains, including gross and fine motor, speech/language, cognition, social/personal, and activities of daily living. The most common conditions present in the pediatric population. About 53 million children (<5 years) have developmental disabilities. Genetic factors are responsible for up to 40% of developmental disability cases. 

An early diagnosis is key to improve the clinical outcome and prevent further complications. In many cases, the diagnosis takes time and involves many specialists. Since children with GDD/ID exhibit mixed and diverse symptoms, and up to two-thirds do not have a single group of symptoms that can point towards a specific diagnosis, it is difficult to establish a diagnosis. As a result, many patients undergo a long diagnostic journey before necessary genetic tests are performed to define the cause of GDD/ID. 

What are the symptoms in each developmental domain? 

Gross and fine motor: delayed ability to sit, crawl or walk; delayed ability to jump, run and climb; inability to grasp objects; inability to hold utensils, work with objects, and draw 

Speech and language: difficulty speaking or delayed speaking; difficulty understanding language; inability to express thoughts 

Cognition: lack of curiosity; short attention span and easily distracted; poor memory; inability to connect actions with consequences; difficulty with problem-solving or logical thinking 

Personal and social development: difficulty communicating or socializing with others; inability to express and control emotions; lower than average IQ test scores; showing repetitive and restricted behavior; showing extreme behavior (unusually fearful, aggressive, shy or sad) 

Activities of daily living: inability to do everyday tasks like getting dressed, eating, brushing teeth, washing hands or going to the bathroom without help 

It is important to note that symptoms vary in type and severity between children and that not all symptoms are listed for each developmental domain. Children should be assessed by their physician and/or genetic counselor. These examples are adapted from https://www.cdc.gov/ncbddd/actearly/milestones. 

Causes of global developmental delay/intellectual disability  

When Possible causes 
Prenatal (before birth) Intrinsic: genetic, central nervous system malformations, metabolic 
Extrinsic: teratogens/toxins (drugs of abuse, medications, etc.), infections 
Perinatal (time frame from one year before to 18 to 24 months after birth) Asphyxia, prematurity, neonatal complications 
Postnatal (first six weeks after birth) Neglect/psychosocial environment, infections, trauma, toxins 

What is the role of genetic factors in GDD/ID cases? 

Genetic factors are responsible for up to 40% of developmental disability cases. According to European guidelines, genetic testing is essential and should become a standardized diagnostic practice in GDD/ID. Among the genetic causes, chromosomal abnormalities are responsible for 25% of cases (trisomy 21 is the most frequent). Fragile X syndrome is the most common monogenic defect associated with GDD/ID (5% of the cases of ID). Many pathways are involved in GDD/ID, including metabolic pathways, neurogenesis, neuronal migration, and synaptic function. 

Who should get genetic testing? 

  • Children <5 years with a significant delay in ≥2 developmental domains (developmental domains include physical, cognitive, speech/language, social and emotional) 
  • Children with an autism spectrum disorder 
  • Children with dysmorphic features 

Why genetic testing? 

Knowing the genetic cause of a disease can help find the right management strategies, as well as inform family members to get tested. Genetic information can help to decide on early rehabilitation services (if possible) and treatment options, identify associated medical risks, thereby improving the patient’s clinical outcome and preventing further complications, and guide reproductive decisions based on recurrence risks. 

Genetic testing approach 

This approach is based on an article by Savatt and Myers published in Frontiers in Pediatrics (2021). 

Step 1: Complete physical examination and collect developmental, medical, and family history. 

  • If a specific diagnosis is suspected, pursue the appropriate specific genetic testing (e.g., PTEN sequencing and deletion/duplication analysis, MECP2 sequencing and deletion/duplication analysis, FMR1 CGG repeat analysis) 
  • If a specific diagnosis is not suspected, proceed to step 2. 

Step 2: Pursue broad examination for causal exonic sequence variants and copy number variants (CNV). 

  • This is most efficiently achieved through exome sequencing (ES) with CNV calling. 
  • If insurance restrictions or laboratory offerings dictate a stepwise approach to CNV analysis and ES, chromosomal microarray (CMA) and ES can be pursued individually. ES should be pursued as the initial evaluation when possible. 
  • ES should be performed using a trio analysis (sequencing of both parents and affected child) when possible, to decrease the number of candidate variants and inform variant classification. 
  • If an etiology is not determined, proceed to step 3. 

Step 3: Complete periodic reanalysis of reported variants and exome data. 

Consider additional genetic testing (e.g., genome sequencing, FMR1 CGG repeat analysis if not already done, cytogenetic testing, if warranted, based on ES/CMA results and clinical findings) and/or referral for medical genetics evaluation if indicated. 

What are common developmental disorders? 

Common developmental disorders include autism spectrum disorders, brain malformations, intellectual disability, and Rett syndrome. 

Autism Spectrum Disorders 

WHAT: Autism Spectrum Disorders (ASD) are among the neuropsychiatric diseases with the greatest heritability. 

HOW: Approximately 20% carry de novo generated CNV. Monogenic causes are found in 3-5%, mostly for syndromes caused by pathogenic variants in single genes that show ASD as a partial symptom. 

MANIFESTATION: Most common comorbidities are developmental disorders or reduced intelligence (about 70%), speech disorders (about 30%), or epilepsy. 

TREATMENT: Multidisciplinary treatment which may involve parent-mediated interventions, and target the child’s individual needs. Interventions may reduce symptoms, improve cognitive ability and daily living skills, and maximize the ability of the child to function and participate in the community. 

PREVALENCE: 1:270 worldwide 

INHERITANCE PATTERN: Unknown, but highly heritable 

Brain Malformations 

WHAT: Disorders in central processes (neuronal proliferation, migration and post migratory cortical organization) during fetal brain development. 

HOW: When genetic causes are considered, there is clinical and genetic overlap. More than 100 genes are known to control these complicated processes. 

MANIFESTATION: Disorders in these developmental steps lead to the formation of various malformations. Disorders are subdivided according to morphology (e.g., lissencephaly), anatomical structures (e.g., pontocerebellar hypoplasias), or functional criteria (e.g., tubulinopathies). 

TREATMENT: Therapies are symptomatic and supportive and depend on the specific symptoms in each individual. 

PREVALENCE: Depends on the syndrome, e.g., 1.2:100,000 births (lissencephaly), >100 cases reported (pontocerebellar hypoplasia), <1:1,000,000 (tubulinopathies). 

INHERITANCE PATTERN: Autosomal dominant or recessive or X-linked, de novo 

Intellectual Disability 

WHAT: Intellectual disability (ID) is defined as an IQ <70, or in severe forms IQ <50. Males are more commonly affected due to X-linked genes. 

HOW: CNVs are responsible for 10-15% of cases with inconspicuous chromosomal analysis. Dominant new mutations contribute to severe ID. Up to 50% of severe non-syndromic developmental disorders are caused by de novo point mutations and small indels with a large degree of genetic heterogeneity. 

MANIFESTATION: Behavioral disorders and/or epilepsies are common. In syndromic forms, a combination of malformations, minor external abnormalities, or characteristic behaviors are observed. However, many patients present with non-characteristic symptoms. 

TREATMENT: Therapies are symptomatic and supportive, including occupational, physical and speech therapy. Interventions may reduce symptoms, improve cognitive ability and daily living skills, and maximize the ability of the child to function and participate in the community. 

PREVALENCE: 2.5-5:1,000 (severe ID), 2-30:1,000 (mild ID) 

INHERITANCE PATTERN: Autosomal dominant, de novo 

Rett Syndrome 

WHAT: Neurodegenerative disorder that occurs predominantly in females. After initially inconspicuous development, children lose previously acquired abilities including meaningful hand movements, speech, and social interaction at between 6 and 18 months of age. 

HOW: Caused by pathogenic variants in the MECP2 gene (mostly de novo). The severity is influenced by the pattern of X inactivation and the type of variant. 

MANIFESTATION: Main symptom is the development of stereotypical hand movements. Other symptoms include delayed growth, microcephaly, gait ataxia, episodes of apnea or hyperpnea, sleep disturbances, progressive scoliosis, and seizures. There are a few affected males who predominantly present with severe neonatal encephalopathy. 

TREATMENT: Medication may be needed for breathing irregularities and motor difficulties. Anticonvulsants are prescribed to control seizures. Regular monitoring for scoliosis and possible heart abnormalities is recommended, as well as occupational, physical and speech therapy. 

PREVALENCE: 1:10,000 females 

INHERITANCE PATTERN: X-linked dominant 

References 

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