1. NGS panel - Genetic testing for X-linked mental retardation

Mental retardation X-linked

June 22, 2017

Clinical features

Intellectual disability (ID), also referred to as mental retardation (MR), is a lifelong disability that presents in infancy/early childhood and is characterized by below-average intelligence and a lack of skills essential for everyday life. People with intellectual disabilities can learn new skills, but they learn them more slowly. Someone with intellectual disability has limitations in two areas:

  • Intellectual functioning, as measured by IQ scores, which refers to a person’s ability to learn, make decisions, and solve problems
  • Adaptive behaviors, the skills necessary for day-to-day life, such as being able to communicate effectively, interact with others, and take care of oneself.

The average IQ (intelligence quotient) is 100, with the majority of people scoring between 85 and 115. A person is considered intellectually disabled if he/she has an IQ of less than 70 1-3.

Mild mental retardation 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. Approximately 2–3% of the population has mild to moderate intellectual disability and 0.5–1% of the population have moderate to severe mental retardation 4, 5.

Considering that mental retardation is significantly more common in males than in females, X-linked gene defects have long been considered to be an important cause of mental retardation. Clinical observations and linkage studies in families revealed that X-linked mental retardation (XLMR) is a highly heterogeneous condition. The most common form of X-linked ID/MR is the Fragile X syndrome, associated with loss of function in the FMR1 gene (mostly due to the trinucleotide repeat expansion and/or abnormal gene methylation) 8. Fragile X syndrome includes several phenotypes:

  • Fragile X syndrome
  • Fragile X-associated tremor/ataxia syndrome (FXTAS)
  • FMR1-related primary ovarian insufficiency.

In addition, other forms of X-linked ID/MR are classified into syndromic and non-syndromic forms. Approximately two thirds of X-linked ID/MR cases are thought to be non-syndromic, e.g. isolated cases of intellectual disability without involvement of other tissues/organs of the body.

Furthermore, mutations in several X-linked ID/MR genes can give rise to both non-syndromic and syndromic forms, indicating that there is no reliable molecular basis for strictly distinguishing between genes for syndromic and non-syndromic MR/ID 4,6,7.

Syndromic forms of X-linked ID/MR include numerous conditions, such as: X-linked alpha thalassemia mental retardation syndrome, Coffin–Lowry syndrome, MASA syndrome, Mental retardation and microcephaly with pontine and cerebellar hypoplasia, ID/MR combined with epilepsy, ataxia, and many other conditions 4, 6.

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 defects have been mapped to a specific region of the X chromosome (Figure 1).

Figure 1: Examples of genes on the X chromosome reported to cause X-linked ID/MR and related diseases. All of these genes are included in the CENTOGENE X-linked mental retardation panel.

Independent of the genetic cause, the majority of patients affected with X-linked ID/MR show similar clinical findings, including the following:

  • Intellectual disability (ID)
  • Dysmorphic features
  • Congenital abnormalities
  • Unexplained seizures
  • Delay in attaining milestones or loss of milestones
  • Hypotonia
  • Abnormal growth
  • Autism spectrum disorder (ASD)

There is no cure for ID/MR except symptomatic therapy and approaches such as speech therapy, psychotherapy, physical therapy, and others. In some non-syndromic ID/MR cases caused by single gene mutations, there is the potential for treatment using various categories of gene therapies. Some of these gene therapies are currently under investigation in animal models.

Based on the most recent literature, CENTOGENE experts have designed a Mental retardation, X-linked panel that includes all relevant genes which have been reported in the most common mutation databases as Mental retardation, X-linked (Table 1). Thus, CENTOGENE offers the Mental retardation, X-linked panel (genes: ABCD1, ACSL4, AFF2, AGTR2, 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, KIAA2022, KDM5C, 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, SRPX2, SYN1, SYP, TIMM8A, TSPAN7, UBE2A, UPF3B, ZCCHC12, ZDHHC9, ZDHHC15, ZNF41, ZNF81, ZNF674, ZNF711), including full gene sequencing and deletion/duplication analysis of selected genes (IDS, IL1RAPL1, L1CAM, MECP2, MID1, MTM1, NDP, NLGN4X, OPHN1, OTC, PAK3, PCDH19, PLP1, PQBP1, RPS6KA3, SLC6A8, TSPAN7). In addition, tests for any of the genes in the Mental retardation, X-linked panel can also be ordered individually, for full gene sequencing and deletion/duplication analysis.

Differential diagnosis

The differential diagnosis of X-linked ID/MR-related disorders – depending on the major symptoms in the initial case – includes the following diseases:

  • Fragile X-syndrome
  • Autistic spectrum behavioral disorders
  • Deafness/hearing loss with or without speech problems
  • Marfan syndrome
  • Lujan-Fryns syndrome.

Testing strategy

CENTOGENE offers advanced, fast and cost-effective strategy to test large NGS panels and diagnose complex phenotypes based on the PCR-free Whole Genome Sequencing and NGS technology. This approach offers an unparalleled advantage by reducing amplification/capture biases and provides sequencing of entire gene at a more uniform coverage.

To confirm/establish the diagnosis, CENTOGENE offers the following testing strategy for mental retardation, X-linked using NGS Panel Genomic targeted towards this specific phenotype:

Step 1: Whole genome sequencing from a single filter card. The sequencing covers the entire genic region (coding region, exon/intron boundaries, intronic and promoter) for all the genes included in the Mental retardation, X-linked panel. Copy Number Variants analysis derived from NGS data is also included.

Step 2: If no mutation is identified after analysis of the Mental retardation, X-linked panel, based on the approval and consent, we further recommend to continue the bioinformatics analysis of the data obtained by whole genome sequencing to cover genes that are either implicated in an overlapping phenotype or could be involved in a similar pathway but not strongly clinically implicated based on the current information in literature.

Referral reasons

The following patients should be tested using CENTOGENE´s Mental retardation, X-linked panel:

  • Males with intellectual disability (ID) who have normal chromosomes, microarray, and fragile X results and X-linked pattern family history
  • Males with ID in the presence or absence of other dysmorphic, neuromuscular, metabolic or behavioral phenotypes that distinguish the patient from unaffected males in the family
  • Females with a family history suggestive of an X-linked disorder and suspected to be carriers when no living males with ID are available to test

Test utility

Sequencing, deletion/duplication of this gene and related genes should be performed in all individuals suspected of having an X-linked ID/MR phenotype. In parallel, other genes reported to be related with this clinical phenotype should also be analyzed for the presence of mutations, due to the overlap in many clinical features caused by those particular genes.

Confirmation of a clinical diagnosis through genetic testing can allow for genetic counseling and may direct medical management. Genetic counseling can provide a patient and/or family with the natural history of the ID/MR, identify at-risk family members, provide reproductive risks as well as preconception/prenatal options, and allow for appropriate referral for patient support and/or resources.

More information on CENTOGENE´s Mental retardation, X-linked panel can be found in our genetic test catalogue.