Mental retardation X-linked
Intellectual disability (ID), also referred to as mental retardation (MR), is a lifelong disability that presents in early childhood and is characterized by below-average intelligence and a lack of skills essential for everyday life. The average IQ (intelligence quotient) is 100, with the majority of people scoring between 85 and 115 1. A person is considered intellectually disabled if he/she has an IQ of less than 701-3. Mild MR is defined as an IQ of 50–70, moderate as an IQ of 35–49, severe as an IQ of 20–34, and profound as an IQ of <20 1-3. Approximately 2–3% of the population has mild to moderate MR and 0.5–1% of the population has moderate to severe MR 4, 5.
More than 140 syndromic forms of X-linked ID/MR have been described so far and in almost half of them causative genetic defects have been identified 4, 6, 7. Numerous X-linked ID/MR underlying genetic defects have been mapped to a specific region of the X chromosome (Figure 1).
1/900 – 1/1,600 in males 1, 2, 4.
Major clinical symptoms for X–linked MR/ID include the following 1-4:
- Intellectual disability (ID)
- Dysmorphic features
- Congenital abnormalities
- Unexplained seizures
- Delay in attaining milestones or loss of milestones
- Abnormal growth
- Autism spectrum disorder (ASD)
- Clinical signs and symptoms characteristic for MR.
- Positive family history of MR.
- Diagnosis confirmed by identification of a pathogenic variant in one of the associated genes: ABCD1, ACSL4, AFF2, AP1S2, ARHGEF6, ARHGEF9, ARX, ATP6AP2, ATP7A, ATRX, BCOR, BRWD3, CASK, CDKL5, CUL4B, DCX, DKC1, DLG3, ELK1, FANCB, FGD1, FLNA, FMR1, FTSJ1, GDI1, GK, GPC3, GRIA3, HCCS, HPRT1, HSD17B10, HUWE1, IDS, IGBP1, IL1RAPL1, KDM5C, KIAA2022, KLF8, L1CAM, LAMP2, MAGT1, MAOA, MBTPS2, MECP2, MED12, MID1, MTM1, NDP, NDUFA1, NHS, NLGN3, NLGN4X, NSDHL, NXF5, OCRL, OFD1, OPHN1, OTC, PAK3, PCDH19, PDHA1, PGK1, PHF6, PHF8, PLP1, PORCN, PQBP1, PRPS1, RAB39B, RPL10, RPS6KA3, SHROOM4, SLC16A2, SLC6A8, SLC9A6, SMC1A, SMS, SOX3, SYN1, SYP, TIMM8A, TSPAN7, UBE2A, UPF3B, ZCCHC12, ZDHHC15, ZDHHC9, ZNF711, ZNF81.
There is no cure for X-linked MR to date, but treatment can relieve symptoms 11.
- Behavioural and educational programs
- Psychiatric care
- Speech therapy for speech delay/impairment
- Obesity is managed with diet, exercise, and behavioral therapies
- Fragile X-syndrome
- Autistic spectrum behavioral disorders
- Deafness/hearing loss with or without speech problems
- Marfan syndrome
- Lujan-Fryns syndrome
To confirm/establish the diagnosis, CENTOGENE offers the following testing strategy for X–linked mental retardation using NGS Panel Genomic:
Step 1: Whole genome sequencing from a single filter card (drop of blood), covering the entire genic region (coding region, exon/intron boundaries, intronic and promoter) for all the genes included in the X–linked mental retardation panel. Copy Number Variants analysis derived from NGS data is also included.
Step 2: If no pathogenic variant is identified in Step1, continue with bioinformatics analysis covering genes that are either implicated or associated with overlapping phenotype or similar pathways.
- Individuals with a positive family history of X–linked mental retardation.
- Individuals with most common symptoms of X–linked mental retardation (regardless of family history).
Confirmation of a clinical diagnosis through genetic testing of X–linked mental retardation can allow for genetic counseling and may direct medical management.
Figure 1. Examples of genes on the X chromosome reported to cause X-linked ID/MR and related diseases*
X-linked intellectual disability, XLID, X-linked mental retardation, XLMR, Mental retardation X-linked, MRX, Intellectual disability, ID, Mental retardation, MR