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Publications about genetic testing for neurological disorders
  1. NGS Panel – Genetic Testing for X-linked Mental Retardation

Mental Retardation X-linked

April 20, 2018

Disease synonyms:

X-linked intellectual disability, XLID, X-linked mental retardation, XLMR, Mental retardation X-linked, MRX, Intellectual disability, ID, Mental retardation, MR


Disease summary:

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
  • Hypotonia
  • 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.


Table 1. Overview of genes associated with Mental retardation X-linked

Gene OMIM (Gene) Associated diseases (OMIM) Inheritance CentoMD® exclusive variant numbers (++)
ABCD1 300371 adrenoleukodystrophy XLR 41
ACSL4 300157 mental retardation 63 XLD 10
AFF2 300806 Mental Retardation, X-Linked, Associated With Fragile Site Fraxe XLR 11
AP1S2 300629 Pettigrew syndrome XLR 3
ARHGEF6 300267 4
ARHGEF9 300429 Epileptic encephalopathy, early infantile, 8 XLR 8
ARX 300382 Proud syndrome; X-linked lissencephaly-2; ARX- related mental retardation; early infantile epileptic encephalopathy 1; Partington X-Linked Mental Retardation Syndrome XL, XLR 8
ATP6AP2 300556 syndromic mental retardation, Hedera type XLR 2
ATP7A 300011 X-linked distal spinal muscular atrophy type 3; Occipital horn syndrome; Menkes disease XLR 19
ATRX 300032 Alpha-Thalassemia Myelodysplasia Syndrome; Alpha-Thalassemia/Mental Retardation Syndrome, X-Linked; Mental retardation-hypotonic facies syndrome, X-linked XLD, XLR 13
BCOR 300485 Microphthalmia, syndromic 2 XLD 10
BRWD3 300553 mental retardation 93 XLR 23
CASK 300172 Fg Syndrome 4; Mental retardation and microcephaly with pontine and cerebellar hypoplasia XLD 17
CDKL5 300203 early infantile epileptic encephalopathy 2 XLD 19
CUL4B 300304 MENTAL RETARDATION, X-LINKED 15 XLR 4
DCX 300121 type 1 lissencephaly XL 6
DKC1 300126 X-linked dyskeratosis congenita XLR 2
DLG3 300189 mental retardation 90 XLR 9
ELK1 311040 1
FANCB 300515 Fanconi anemia of complementation group B XLR 6
FGD1 300546 Aarskog-Scott syndrome XLR 14
FLNA 300017 Congenital short bowel syndrome; Heterotopia, periventricular / X-linked periventricular heterotopia; Terminal osseous dysplasia; FG syndrome 2; Otopalatodigital syndrome, type II; Frontometaphyseal dysplasia; Melnick-Needles syndrome; otopalatodigital syndrome type I; Cardiac valvular dysplasia, X-linked XL, XLD, XLR 34
FMR1 309550 fragile X tremor/ataxia syndrome; fragile X mental retardation syndrome; premature ovarian failure type 1 XL, XLD 51
FTSJ1 300499 MENTAL RETARDATION, X-LINKED 9 XLR 4
GDI1 300104 mental retardation 41 XLD 1
GK 300474 Glycerol kinase deficiency XLR 14
GPC3 300037 Wilms tumor, type 1; Simpson-Golabi-Behmel syndrome, type 1 XLR 6
GRIA3 305915 syndromic mental retardation, Wu type XLR 17
HCCS 300056 Microphthalmia, syndromic 7 XLD 2
HPRT1 308000 Lesch-Nyhan syndrome; Kelley-Seegmiller syndrome XLR 9
HSD17B10 300256 HSD10 mitochondrial disease XLD 7
HUWE1 300697 XL 22
IDS 300823 mucopolysaccharidosis type II XLR 201
IGBP1 300139 mental retardation 28 XLR 2
IL1RAPL1 300206 mental retardation 21 XLR 7
KDM5C 314690 syndromic mental retardation - Claes-Jensen type XLR 11
KLF8 300286 3
L1CAM 308840 spastic paraplegia type 1; partial agenesis of the corpus callosum; hydrocephalus with stenosis of the aqueduct of Sylvius XLR 13
LAMP2 309060 Danon disease XLD 10
MAGT1 300715 Immunodeficiency, X-Linked, With Magnesium Defect, Epstein-Barr Virus Infection, And Neoplasia 1
MAOA 309850 Brunner syndrome XLR 8
MBTPS2 300294 IFAP syndrome with or without BRESHECK syndrome; Keratosis follicularis spinulosa decalvans, X-linked XLR 4
MECP2 300005 MENTAL RETARDATION, X-LINKED 13; Autism susceptibility, X-linked 3; severe neonatal encephalopathy; Rett syndrome XL, XLD, XLR 18
MED12 300188 Opitz-Kaveggia syndrome /FG syndrome-1; Lujan-Fryns syndrome XLR 21
MID1 300552 Opitz GBBB syndrome, X-linked XLR 6
MTM1 300415 X-linked myotubular myopathy XLR 7
NDP 300658 Exudative Vitreoretinopathy 2, X-Linked; Norrie disease XLR 6
NDUFA1 300078 XLR 10
NEXMIF 300524 mental retardation 98 XLD 14
NHS 300457 Nance-Horan syndrome XL, XLD 8
NLGN3 300336 Autism, Susceptibility To, X-Linked 1; Asperger Syndrome, X-Linked, Susceptibility To, 1 XL 5
NLGN4X 300427 Autism, Susceptibility To, X-Linked 2; Asperger Syndrome, X-Linked, Susceptibility To, 2 XL 9
NSDHL 300275 CK syndrome; CHILD syndrome XLD, XLR 4
NXF5 300319 6
OCRL 300535 Dent disease type 2; Lowe oculocerebrorenal syndrome XLR 10
OFD1 300170 Joubert syndrome 10; oral-facial-digital syndrome 1 XLD, XLR 20
OPHN1 300127 mental retardation 60 XLR 15
OTC 300461 ornithine transcarbamylase deficiency XLR 18
PAK3 300142 mental retardation 30 XLR 3
PCDH19 300460 early infantile epileptic encephalopathy type 9 XL 14
PDHA1 300502 Pyruvate dehydrogenase E1-alpha deficiency XLD 15
PGK1 311800 Phosphoglycerate kinase 1 deficiency XLR 5
PHF6 300414 Borjeson-Forssman-Lehmann syndrome XLR 3
PHF8 300560 syndromic mental retardation, Siderius type XLR 9
PLP1 300401 Pelizaeus-Merzbacher disease; spastic paraplegia 2 XLR 19
PORCN 300651 Focal dermal hypoplasia XLD 4
PQBP1 300463 Renpenning Syndrome 1 XLR 2
PRPS1 311850 Phosphoribosylpyrophosphate synthetase superactivity; Arts syndrome; deafness type 1; type X5 Charcot-Marie-Tooth XL, XLR 5
RAB39B 300774 mental retardation 72 XLR 2
RPL10 312173 Autism, susceptibility to, X-linked 5 XLR 1
RPS6KA3 300075 MENTAL RETARDATION, X-LINKED 19; Coffin-Lowry syndrome XLD 15
SHROOM4 300579 Stocco dos Santos X-linked mental retardation syndrome XL 5
SLC16A2 300095 Allan-Herndon-Dudley syndrome XL 9
SLC6A8 300036 Cerebral creatine deficiency syndrome type 1 XLR 20
SLC9A6 300231 Christianson type of X-linked syndromic mental retardation XLD 13
SMC1A 300040 Cornelia de Lange syndrome 2 XLD 10
SMS 300105 Snyder-Robinson mental retardation syndrome XLR 5
SOX3 313430 Mental Retardation, X-Linked, With Panhypopituitarism; Panhypopituitarism, X-linked XL 3
SYN1 313440 Epilepsy, X-linked, with variable learning disabilities and behavior disorders XLD, XLR 3
SYP 313475 mental retardation 96 XLR 5
TIMM8A 300356 Mohr-Tranebjaerg syndrome XLR 3
TSPAN7 300096 mental retardation 58 XLR 4
UBE2A 312180 syndromic mental retardation, Nascimento type XLR 3
UPF3B 300298 mental retardation 14 XLR 5
ZCCHC12 300701 0
ZDHHC15 300576 mental retardation 91 XLD 3
ZDHHC9 300646 syndromic mental retardation, ZDHHC9-related 2
ZNF711 314990 mental retardation 97 XL 4
ZNF81 314998 0

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.