Guideline for Genetic Investigation and

Management of Intellectual Disability

 Guideline for Genetic Investigation and Management of Intellectual

Disability
Document Title:

Document Ref. Number: DOH/GL/ID/V1 Version V1

New / Revised New

Publication Date: 01 June 2023

Effective Date June 2023

Document Control DoH Strategy Sector

- DoH licensed Healthcare Providers

Applies To: - DoH authorized Health Payers.
- All Health Insurance products and schemes, as applicable.

Owner Research and Innovation Center

Revision Date June 2026

The fixed period that is expected to complete the review of the

Revision Period
regulation

Contact RIC@doh.gov.ae

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 1. Guideline Purpose and Brief

Intellectual disability (ID) is frequent, affecting 2–3% of children and adults worldwide. ID is the disease
category with one of the largest health care costs. The etiology of ID is diverse, including infectious,
traumatic and toxic causes. Genetic etiologies constitute the most frequent cause and are
demonstrable in more than 50% of individuals with ID, ranging from numeric and structural
chromosomal abnormalities and submicroscopic copy number variants to methylation abnormalities,
and to single gene defects.

Given high degree of consanguinity in the UAE population, there is a high prevalence of autosomal
recessive genetic disorders, and this reflects on the group with intellectual disability.
A considerable proportion of treatable IDs (62%) can be reliably detected through a panel of metabolic
screening tests on blood and urine. The incidence of the individual treatable IEMs is rare, ranging from
1:10,000 to less than 1:200,000, though their recognition is of importance however, treatability
overweighs the rare nature of these conditions. The majority of effective treatments are nutritional,
which are relatively affordable, widely available and effective. In addition to treatment, identifying the
genetic etiology will guide patient’s overall management plan and facilitate accurate genetic
counseling.

This Guideline aims to provide general guidance for the etiological investigation of any individual who
has a confirmed clinical diagnosis of developmental delay or intellectual disability in order to reach a
genetic diagnosis. This will provide immense benefits which includes but is not limited to:
1. Determine the exact genetic etiology of the neurodevelopmental disorder
2. Avoiding unnecessary diagnostic tests and multiple physician visits
3. Provides information regarding the short- and long-term prognosis
4. Facilitates the medical management and provides better access to services by understanding
the potential areas in need and opportunities for increased support
5. Provides the ability to identify, treat, and/or prevent medical comorbidities at the time of
diagnosis, as well as conditions that may develop later in life
6. Access to etiology specific treatments or enrolment into potential therapies in clinical trials
7. Refine recurrence risk counseling for the family to inform reproductive decision making and
enable prenatal diagnosis
8. Screening of other siblings at risk to identify those affected with the neurodevelopmental
disorders and initiate beneficial behavioral treatments and therapies at earlier age

This guideline is intended for use by clinical specialties in metabolic and clinical genetics for the
diagnosis and management of global developmental delay and/or intellectual disability.

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 2. Definitions and Abbreviations1

No. Term / Abbreviation Definition

is a life-long and debilitating condition applied to age ≥

5 years and manifesting before age 18 years,
historically referred to as ‘mental retardation’ with
intellectual functioning level (IQ) less than 70 to 75
and significant limitations in two or more adaptive
Intellectual disability (ID) skills.
2.1 ID is often associated with behavioral problems
(autism, hyperactivity, aggressivity and self-injurious
behavior), epilepsy and other neurological disabilities,
all resulting in psychological, social and economic
burdens.

is applied to children age < 5 years with significant

delay (= performance two standard deviations or more
below the mean on age‐appropriate, standardized
Global developmental delay
2.2 (DD) norm‐referenced testing) in two or more
developmental domains including gross/fine motor
skills, speech/language, cognition, social/personal,
activities of daily living.

3. Guideline Content

1. Diagnosis and Investigation:

The Geneticist will conduct a thorough assessment including detailed history, obtain a 3-
generation family pedigree and perform a complete physical examination. Based on this, the
geneticist will determine if a specific diagnosis is suspected. If this is the case, specific metabolic
or genetic testing will be performed accordingly (refer to Appendix 1 and 2).

Otherwise, the geneticist will proceed to 1st tier investigations which includes metabolic
investigations (refer to Appendix 1), whole exome (and/or Genome) sequencing with or without a
chromosomal microarray. Second tier testing (refer to Appendix 2) may additionally be
considered.

If results of investigations provide a clear diagnosis, then a specific management plan will be
implemented (refer to Appendix 3) as well as accurate genetic counseling provided.

However, if results of investigations do not provide a clear diagnosis, then review and further
expanded genetic and metabolic testing should be considered.

1 NOTE: Here we will use the term ID collectively for both ID and DD.

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Figure 1 Diagnostic pathway

All individuals with developmental delay/intellectual disability should undergo a detailed

neurodevelopmental assessment and psychoeducational evaluation including IQ testing.

2. Management:

Management is usually lifelong, should be implemented according to the diagnosis, and may
include the following:

1. Metabolic diet management through a metabolic dietician consultation and special

metabolic diet formulas and supplies.
2. Medications which may include enzyme replacement therapy, co-factors, vitamins, nitrogen
scavengers etc.
3. Lab monitoring may be needed. The investigations and frequency judged clinically and
based on the diagnosis.
4. Genetic counseling, parental carrier screening as well as genetic screening of at-risk family
members. This may also include early prenatal testing of at-risk fetus in future pregnancy.

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 4. Appendices

Appendix 1: Metabolic screening labs

1. CBC with differential

2. Electrolytes, Urea, Creatinine, Blood gas
3.Glucose
4. Ammonia
5. Lactate
6. Homocysteine
7. Uric Acid
8. Creatine Kinase
9. Liver enzymes: AST and ALT
10. Calcium, Phosphate and ALP
11. Albumin, Bilirubin and INR
12. Lipid panel
13. Plasma amino acid quantitative
14. Urine amino acid
15. Plasma acylcarnitine profile
16. Plasma total and free carnitine levels
17. Urine organic acid profile
18. Urine analysis

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Appendix 2: Second Tier Testing

1.Chromosomal Karyotype
2. Fragile X testing
3. Enzymatic assays – multiple enzymes including GALT, biotinidase, lysosomal enzymes etc.

4.Serum copper, Ceruloplasmin

5.Urine bile salts
6.Urine mucopolysaccharides
7.Urine oligosaccharides
8.Urine sulfatides
9.Urine orotic acid
10. Urine succinylacetone
11. Plasma methylmalonic acid
12. Plasma CDG screen by TIEF
13. Plasma very long chain fatty acids
14. Plasma phytanic acid, plasmalogens
15. Plasma DHPR
16. Plasma essential fatty acid profile
17. Urine pterins
18. Urine purine and pyrimidines
19. Urine alpha-amino adipic semi-aldehyde
20. Urine creatine panel
21. Urine sialic
22. CSF amino acids
23. CSF neurotransmitters ..etc.
24. Metabolomic studies
25. Vitamin levels i.e: Vitamin B12 ..etc.
26. Fibroblast fatty acid oxidation studies
27. Mitochondrial Respiratory Chain Enzyme Analysis
(fibroblast or muscle)
28. Complementation studies on fibroblast
29. RNA Sequencing (Panel, or gene specific)
30. Disease Biomarkers (example: Lyso-GB1..etc)
31. Single gene sequencing

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 Appendix 3: Management

Medications Dietary interventions and Amino acid Enzyme

metabolic formulas supplementation Replacement
therapy
Levocarnitine Essential amino acid Arginine Imiglucerase,
formula: Cyclinex-1/2 Taliglucerase,
Velaglucerase
Sodium Benzoate Methionine and Valine Free: Citrulline Elosulfase
Propimex-1/2
Sodium or Glycerol Leucine restricted: Valex-1/2 Serine Galsulfase
phenylbutyrate
Nitisinone Phenylalanine free formula: Glycine Alglucosidase alfa,
Phenex-1/2 Avalglucosidase alfa
Carglumic acid Tyrosine restricted formula: Cysteine Laronidase
Tyrex-1/2
Vitamins: Biotin, Branched chain amino acid Lysine Idursulfase
free formula: Ketonex-1/2
Thiamine, Folinic acid,
Riboflavin, Pyridoxine,
Pyridoxal-5-phosphate, Folic
acid, Vitamin E, Vitamin A,
Vitamin C

Betaine Lysine restricted formula: Isoleucine Velmanase alfa

Glutarex-1/2
Hydroxycobalamin Modified cornstarch: Valine Sebelipase alfa
Glycosade
Tetrahydrobiopterin Cysteine restricted diet Agalsidase alfa,
agalsidase beta
Sapropterin
L-dopa/carbidopa Ketogenic diet: Ketocal Pegvaliase
5-Hydroxytryptophan Prophree Oilpudase alfa
Copper histidine Doucal
CoenzymeQ10 Maxijule
Lipoic acid MCT oil
Cholic Acid Liquagen
Miglustat
Eliglustat
Dextromethorphan
Cysteamine oral/eye drops

Triheptanoin

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 BIBLIOGRAPHY

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