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; Adrenomyeloneuropathy, adult XL R 35
ACSL4 300157 Mental retardation, X-linked 63 XL D 7
AFF2 300806 Mental retardation, X-linked, FRAXE type XL R 9
AP1S2 300629 Mental retardation, X-linked syndromic 5 XL R 2
ARHGEF6 300267 ?Mental retardation, X-linked 46 XL R 4
ARHGEF9 300429 Epileptic encephalopathy, early infantile, 8 XL R 7
ARX 300382 Proud syndrome; Hydranencephaly with abnormal genitalia; Lissencephaly, X-linked 2; Mental retardation, X-linked 29 and others; Epileptic encephalopathy, early infantile, 1; Partington syndrome XL, XL R 7
ATP6AP2 300556 Mental retardation, X-linked, syndromic, Hedera type; ?Parkinsonism with spasticity, X-linked XL R 2
ATP7A 300011 Spinal muscular atrophy, distal, X-linked 3; Occipital horn syndrome; Menkes disease XL R 15
ATRX 300032 Alpha-thalassemia myelodysplasia syndrome, somatic; Alpha-thalassemia/mental retardation syndrome; Mental retardation-hypotonic facies syndrome, X-linked XL D, XL R 11
BCOR 300485 Microphthalmia, syndromic 2 XL D 7
BRWD3 300553 Mental retardation, X-linked 93 XL R 21
CASK 300172 FG syndrome 4; Mental retardation, with or without nystagmus; Mental retardation and microcephaly with pontine and cerebellar hypoplasia XL D 17
CDKL5 300203 Epileptic encephalopathy, early infantile, 2 XL D 18
CUL4B 300304 Mental retardation, X-linked, syndromic 15 (Cabezas type) XL R 4
DCX 300121 Lissencephaly, X-linked; Subcortical laminal heterotopia, X-linked XL 5
DKC1 300126 Dyskeratosis congenita, X-linked XL R 2
DLG3 300189 Mental retardation, X-linked 90 XL R 9
ELK1 311040 1
FANCB 300515 Fanconi anemia, complementation group B 6
FGD1 300546 Aarskog-Scott syndrome; Mental retardation, X-linked syndromic 16 XL R 11
FLNA 300017 Congenital short bowel syndrome; Intestinal pseudoobstruction, neuronal; Heterotopia, periventricular; Terminal osseous dysplasia; ?FG syndrome 2; Otopalatodigital syndrome, type II; Frontometaphyseal dysplasia 1; Melnick-Needles syndrome; Otopalatodigital syndrome, type I; Cardiac valvular dysplasia, X-linked XL, XL D, XL R 34
FMR1 309550 Fragile X tremor/ataxia syndrome; Fragile X syndrome; Premature ovarian failure 1 XL, XL D 46
FTSJ1 300499 Mental retardation, X-linked 9/44 XL R 4
GDI1 300104 Mental retardation, X-linked 41 XL D 1
GK 300474 Glycerol kinase deficiency XL R 9
GPC3 300037 Wilms tumor, somatic; Simpson-Golabi-Behmel syndrome, type 1 XL R 5
GRIA3 305915 Mental retardation, X-linked 94 XL R 16
HCCS 300056 Linear skin defects with multiple congenital anomalies 1 XL D 2
HPRT1 308000 Lesch-Nyhan syndrome; HPRT-related gout XL R 7
HSD17B10 300256 HSD10 mitochondrial disease XL D 7
HUWE1 300697 Mental retardation, X-linked syndromic, Turner type 17
IDS 300823 Mucopolysaccharidosis II XL R 190
IGBP1 300139 Corpus callosum, agenesis of, with mental retardation, ocular coloboma and micrognathia XL R 1
IL1RAPL1 300206 Mental retardation, X-linked 21/34 XL R 7
KDM5C 314690 Mental retardation, X-linked, syndromic, Claes-Jensen type XL R 11
KLF8 300286 3
L1CAM 308840 CRASH syndrome; MASA syndrome; Corpus callosum, partial agenesis of; Hydrocephalus due to aqueductal stenosis; Hydrocephalus with Hirschsprung disease; Hydrocephalus with congenital idiopathic intestinal pseudoobstruction XL R 12
LAMP2 309060 Danon disease XL D 10
MAGT1 300715 Immunodeficiency, X-linked, with magnesium defect, Epstein-Barr virus infection and neoplasia 0
MAOA 309850 Antisocial behavior; Brunner syndrome XL R 7
MBTPS2 300294 ?Olmsted syndrome, X-linked; IFAP syndrome with or without BRESHECK syndrome; Keratosis follicularis spinulosa decalvans, X-linked XL R 4
MECP2 300005 Mental retardation, X-linked, syndromic 13; Mental retardation, X-linked syndromic, Lubs type; Autism susceptibility, X-linked 3; Encephalopathy, neonatal severe; Rett syndrome; Rett syndrome, atypical; Rett syndrome, preserved speech variant Isolated cases, MF, XL, XL D, XL R 16
MED12 300188 Ohdo syndrome, X-linked; Opitz-Kaveggia syndrome; Lujan-Fryns syndrome XL R 18
MID1 300552 Opitz GBBB syndrome, type I XL R 7
MTM1 300415 Myotubular myopathy, X-linked XL R 7
NDP 300658 Exudative vitreoretinopathy 2, X-linked; Norrie disease XL R 6
NDUFA1 300078 Mitochondrial complex I deficiency AR, M, XL D 10
NEXMIF 300524 Mental retardation, X-linked 98 XL D 9
NHS 300457 Cataract 40, X-linked; Nance-Horan syndrome XL, XL D 6
NLGN3 300336 Autism susceptibility, X-linked 1; Asperger syndrome susceptibility, X-linked 1 Isolated cases, MF, XL 5
NLGN4X 300427 Autism susceptibility, X-linked 2; Mental retardation, X-linked; Asperger syndrome susceptibility, X-linked 2 Isolated cases, MF, XL 9
NSDHL 300275 CK syndrome; CHILD syndrome XL D, XL R 4
NXF5 300319 6
OCRL 300535 Dent disease 2; Lowe syndrome XL R 10
OFD1 300170 Simpson-Golabi-Behmel syndrome, type 2; ?Retinitis pigmentosa 23; Joubert syndrome 10; Orofaciodigital syndrome I XL D, XL R 18
OPHN1 300127 Mental retardation, X-linked, with cerebellar hypoplasia and distinctive facial appearance XL R 15
OTC 300461 Ornithine transcarbamylase deficiency XL R 15
PAK3 300142 Mental retardation, X-linked 30/47 XL R 3
PCDH19 300460 Epileptic encephalopathy, early infantile, 9 XL 11
PDHA1 300502 Pyruvate dehydrogenase E1-alpha deficiency XL D 13
PGK1 311800 Phosphoglycerate kinase 1 deficiency XL R 5
PHF6 300414 Borjeson-Forssman-Lehmann syndrome XL R 3
PHF8 300560 Mental retardation syndrome, X-linked, Siderius type XL R 9
PLP1 300401 Pelizaeus-Merzbacher disease; Spastic paraplegia 2, X-linked XL R 17
PORCN 300651 Focal dermal hypoplasia XL D 5
PQBP1 300463 Renpenning syndrome XL R 3
PRPS1 311850 Gout, PRPS-related; Phosphoribosylpyrophosphate synthetase superactivity; Arts syndrome; Deafness, X-linked 1; Charcot-Marie-Tooth disease, X-linked recessive, 5 XL, XL R 5
RAB39B 300774 Mental retardation, X-linked 72; ?Waisman syndrome XL R 2
RPL10 312173 Autism, susceptibility to, X-linked 5; Mental retardation, X-linked, syndromic, 35 XL R 1
RPS6KA3 300075 Mental retardation, X-linked 19; Coffin-Lowry syndrome Isolated cases, XL D 15
SHROOM4 300579 Stocco dos Santos X-linked mental retardation syndrome XL 5
SLC16A2 300095 Allan-Herndon-Dudley syndrome XL 7
SLC6A8 300036 Cerebral creatine deficiency syndrome 1 XL R 20
SLC9A6 300231 Mental retardation, X-linked syndromic, Christianson type XL D 12
SMC1A 300040 Cornelia de Lange syndrome 2 XL D 9
SMS 300105 Mental retardation, X-linked, Snyder-Robinson type XL R 5
SOX3 313430 Mental retardation, X-linked, with isolated growth hormone deficiency; Panhypopituitarism, X-linked XL 2
SYN1 313440 Epilepsy, X-linked, with variable learning disabilities and behavior disorders XL D, XL R 2
SYP 313475 Mental retardation, X-linked 96 XL D 2
TIMM8A 300356 Mohr-Tranebjaerg syndrome XL R 3
TSPAN7 300096 Mental retardation, X-linked 58 XL R 3
UBE2A 312180 Mental retardation, X-linked syndromic, Nascimento-type XL R 2
UPF3B 300298 Mental retardation, X-linked, syndromic 14 XL R 5
ZCCHC12 300701 0
ZDHHC15 300576 ?Mental retardation, X-linked 91 XL D 3
ZDHHC9 300646 Mental retardation, X-linked syndromic, Raymond type 2
ZNF711 314990 Mental retardation, X-linked 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.