Entry - #616944 - INTELLECTUAL DEVELOPMENTAL DISORDER, AUTOSOMAL DOMINANT 41; MRD41 - OMIM

 
ICD+
# 616944

INTELLECTUAL DEVELOPMENTAL DISORDER, AUTOSOMAL DOMINANT 41; MRD41


Alternative titles; symbols

MENTAL RETARDATION, AUTOSOMAL DOMINANT 41


Phenotype-Gene Relationships

Location Phenotype Phenotype
MIM number 		Inheritance Phenotype
mapping key 		Gene/Locus Gene/Locus
MIM number
3q26.32 Intellectual developmental disorder, autosomal dominant 41 616944 AD 3 TBL1XR1 608628
Clinical Synopsis
 
Phenotypic Series
 

INHERITANCE
- Autosomal dominant
HEAD & NECK
Face
- Dysmorphic features, nonspecific (in some patients)
NEUROLOGIC
Central Nervous System
- Delayed psychomotor development
- Intellectual disability, variable severity
- Delayed language
- Seizures (1 patient)
Behavioral Psychiatric Manifestations
- Autistic features (in some patients)
MISCELLANEOUS
- De novo mutation
- Variable phenotype
MOLECULAR BASIS
- Caused by mutation in the transducin-beta-like 1 receptor 1 gene (TBL1XR1, 608628.0001)
▲ Close
Intellectual developmental disorder, autosomal dominant - PS156200 - 66 Entries
Location Phenotype Inheritance Phenotype
mapping key 		Phenotype
MIM number 		Gene/Locus Gene/Locus
MIM number
1p36.11 Coffin-Siris syndrome 2 AD 3 614607 ARID1A 603024
1q21.3 White-Sutton syndrome AD 3 616364 POGZ 614787
1q21.3 GAND syndrome AD 3 615074 GATAD2B 614998
1q22 Intellectual developmental disorder, autosomal dominant 52 AD 3 617796 ASH1L 607999
1q44 Intellectual developmental disorder, autosomal dominant 22 AD 3 612337 ZBTB18 608433
2p25.3 Intellectual developmental disorder, autosomal dominant 39 AD 3 616521 MYT1L 613084
2q11.2 ?Intellectual developmental disorder, autosomal dominant 69 AD 3 617863 LMAN2L 609552
2q23.1 Intellectual developmental disorder, autosomal dominant 1 AD 3 156200 MBD5 611472
3p25.3 Intellectual developmental disorder, autosomal dominant 23 AD 3 615761 SETD5 615743
3p21.31 Intellectual developmental disorder, autosomal dominant 70 AD 3 620157 SETD2 612778
3q22.3 Intellectual developmental disorder, autosomal dominant 47 AD 3 617635 STAG1 604358
3q26.32 Intellectual developmental disorder, autosomal dominant 41 AD 3 616944 TBL1XR1 608628
3q27.1 Intellectual developmental disorder 60 with seizures AD 3 618587 AP2M1 601024
4q31.1 Intellectual developmental disorder, autosomal dominant 50, with behavioral abnormalities AD 3 617787 NAA15 608000
5p15.2 Intellectual developmental disorder, autosomal dominant 63, with macrocephaly AD 3 618825 TRIO 601893
5p15.2 Intellectual developmental disorder, autosomal dominant 44, with microcephaly AD 3 617061 TRIO 601893
5q13.3 Intellectual developmental disorder, autosomal dominant 34 AD 3 616351 COL4A3BP 604677
5q32 Intellectual developmental disorder, autosomal dominant 53 AD 3 617798 CAMK2A 114078
5q33.2 Intellectual developmental disorder, autosomal dominant 67 AD 3 619927 GRIA1 138248
6p21.32 Intellectual developmental disorder, autosomal dominant 5 AD 3 612621 SYNGAP1 603384
6q13 Intellectual developmental disorder, autosomal dominant 46 AD 3 617601 KCNQ5 607357
6q14.3 Intellectual developmental disorder, autosomal dominant 64 AD 3 619188 ZNF292 616213
6q22.1 Intellectual developmental disorder, autosomal dominant 55, with seizures AD 3 617831 NUS1 610463
6q24.2 Intellectual developmental disorder, autosomal dominant 43 AD 3 616977 HIVEP2 143054
6q25.3 Coffin-Siris syndrome 1 AD 3 135900 ARID1B 614556
7p22.1 Intellectual developmental disorder, autosomal dominant 48 AD 3 617751 RAC1 602048
7p13 Intellectual developmental disorder, autosomal dominant 54 AD 3 617799 CAMK2B 607707
7q11.22 Intellectual developmental disorder, autosomal dominant 26 AD 3 615834 KIAA0442 607270
7q36.2 Intellectual developmental disorder, autosomal dominant 33 AD 3 616311 DPP6 126141
9p24 Intellectual developmental disorder, autosomal dominant 2 AD 4 614113 MRD2 614113
9q34.11 Intellectual developmental disorder, autosomal dominant 58 AD 3 618106 SET 600960
9q34.3 Kleefstra syndrome 1 AD 3 610253 EHMT1 607001
10p15.3 Intellectual developmental disorder, autosomal dominant 30 AD 3 616083 ZMYND11 608668
10q22.2 Intellectual developmental disorder, autosomal dominant 59 AD 3 618522 CAMK2G 602123
11p15.5 Vulto-van Silfout-de Vries syndrome AD 3 615828 DEAF1 602635
11q13.1 Coffin-Siris syndrome 7 AD 3 618027 DPF2 601671
11q13.1-q13.2 Schuurs-Hoeijmakers syndrome AD 3 615009 PACS1 607492
11q13.2 Intellectual developmental disorder, autosomal dominant 51 AD 3 617788 KMT5B 610881
11q24.2 Intellectual developmental disorder, autosomal dominant 4 AD 2 612581 MRD4 612581
12p13.1 Intellectual developmental disorder, autosomal dominant 6, with or without seizures AD 3 613970 GRIN2B 138252
12q12 Coffin-Siris syndrome 6 AD 3 617808 ARID2 609539
12q13.12 Intellectual developmental disorder, autosomal dominant, FRA12A type AD 3 136630 DIP2B 611379
12q13.2 Coffin-Siris syndrome 8 AD 3 618362 SMARCC2 601734
12q21.33 Intellectual developmental disorder, autosomal dominant 66 AD 3 619910 ATP2B1 108731
14q11.2 Intellectual developmental disorder, autosomal dominant 74 AD 3 620688 HNRNPC 164020
15q21.3 Intellectual developmental disorder, autosomal dominant 71, with behavioral abnormalities AD 3 620330 RFX7 612660
16p13.3 Intellectual developmental disorder, autosomal dominant 72 AD 3 620439 SRRM2 606032
16q22.1 Intellectual developmental disorder, autosomal dominant 21 AD 3 615502 CTCF 604167
16q24.3 Intellectual developmental disorder, autosomal dominant 3 AD 3 612580 CDH15 114019
17p13.1 Intellectual developmental disorder, autosomal dominant 62 AD 3 618793 DLG4 602887
17q21.2 Coffin-Siris syndrome 5 AD 3 616938 SMARCE1 603111
17q21.31 Koolen-De Vries syndrome AD 3 610443 KANSL1 612452
17q23.1 Intellectual developmental disorder, autosomal dominant 56 AD 3 617854 CLTC 118955
17q23.2 Intellectual developmental disorder, autosomal dominant 61 AD 3 618009 MED13 603808
17q23.2 Intellectual developmental disorder, autosomal dominant 57 AD 3 618050 TLK2 608439
18q12.3 Intellectual developmental disorder, autosomal dominant 29 AD 3 616078 SETBP1 611060
19p13.3 Intellectual developmental disorder, autosomal dominant 65 AD 3 619320 KDM4B 609765
19p13.2 Coffin-Siris syndrome 4 AD 3 614609 SMARCA4 603254
19q13.12 Intellectual developmental disorder, autosomal dominant 68 AD 3 619934 KMT2B 606834
19q13.2 Intellectual developmental disorder, autosomal dominant 45 AD 3 617600 CIC 612082
20q11.23 ?Intellectual developmental disorder, autosomal dominant 11 AD 3 614257 EPB41L1 602879
20q13.33 Intellectual developmental disorder, autosomal dominant 73 AD 3 620450 TAF4 601796
20q13.33 Intellectual developmental disorder, autosomal dominant 38 AD 3 616393 EEF1A2 602959
21q22.13 Intellectual developmental disorder, autosomal dominant 7 AD 3 614104 DYRK1A 600855
22q11.23 Coffin-Siris syndrome 3 AD 3 614608 SMARCB1 601607
22q12.3 ?Intellectual developmental disorder, autosomal dominant 10 AD 3 614256 CACNG2 602911
▲ Close

▼ TEXT

A number sign (#) is used with this entry because of evidence that autosomal dominant intellectual developmental disorder-41 (MRD41) is caused by heterozygous mutation in the TBL1XR1 gene (608628) on chromosome 3q26.

▼ Clinical Features

Saitsu et al. (2014) reported a 5-year-old Japanese girl with intellectual disability and autistic features. She developed infantile spasms at age 5 months. Electroencephalogram (EEG) later showed hypsarrhythmia and brain MRI revealed no structural brain anomalies; these features were consistent with a clinical diagnosis of West syndrome. She had no eye fixation or pursuit at age 7 months and had mild dysmorphic features. At age 8 months, she developed stereotypic hand movements; at age 5 years, she could walk with support, had a developmental quotient of 13, and showed autistic features.

Clinical Variability

Armour et al. (2009) reported a 15-year-old boy with global developmental delay, early-onset spastic paraparesis with increased lower limb muscle tone and bilateral extensor plantar responses, and dysfunctional bladder voiding with nocturnal enuresis. Physical examination at age 15 years showed microcephaly and small hands and feet with marked brachydactyly, particularly of the second and fifth fingers. Thumbs and big toes were short and broad, and radiographs showed short metacarpals and phalanges. He had a long oval face, facial asymmetry, small chin, dysarthria with hypernasal speech, and high-arched palate. One radiograph available from childhood showed cone-shaped epiphysis of the proximal phalanx of the right great toe. The patient also had Tourette syndrome (137580), which was also present in his otherwise unaffected brother. Karyotype and chromosomal microarray analyses were normal. Armour et al. (2016) concluded that the additional features in this patient may not have been caused by his TBL1XR1 mutation; see MOLECULAR GENETICS.


▼ Cytogenetics

Tabet et al. (2014) reported a 6-year-old girl with nonspecific mild to moderate intellectual disability associated with a de novo heterozygous 1.6-Mb deletion on chromosome 3q26.31-q26.32 involving the TBL1XR1 gene and predicted to result in haploinsufficiency. Brain MRI and EEG were normal, and she did not have autistic features.

Pons et al. (2015) reported an 8-year-old girl and her mother who had the same 708-kb interstitial deletion on chromosome 3q26.32 encompassing only the TBL1XR1 gene; the deletion occurred de novo in the mother. Both individuals had mild to moderate intellectual disability, speech delay, and dysmorphic facial features, including synophrys, mild hypotelorism, depression of the nasal bridge, short nose with anteverted nares, long philtrum, pointed chin, low-set ears, and dental crowding. Clinodactyly and sandal gap were also noted. Autistic features were not present.


▼ Molecular Genetics

In a 5-year-old Japanese girl with MRD41, Saitsu et al. (2014) identified a de novo heterozygous missense mutation in the TBL1XR1 gene (G70D; 608628.0001). The mutation was found by whole-exome sequencing. Functional studies of the variant were not performed.

In a girl with MRD41 and autistic features, O'Roak et al. (2012) identified a de novo heterozygous missense mutation in the TBL1XR1 gene (L282P; 608628.0002). The patient had a nonverbal IQ of 47. Functional studies of the variant were not performed. The patient was from a cohort of 209 parent-child trios exhibiting sporadic autism spectrum disorders who underwent whole-exome sequencing. The same patient was also reported by O'Roak et al. (2012).

In a boy with MRD41 and autistic features, O'Roak et al. (2012) identified a de novo heterozygous truncating mutation in the TBL1XR1 gene (608628.0003). Functional studies of the variant were not performed. The patient was from a cohort of 2,446 autism spectrum disorder probands who underwent sequencing of 44 candidate genes.

In a patient with MRD41, Armour et al. (2016) identified a de novo heterozygous missense mutation in the TBL1XR1 gene (Y245C; 608628.0004). The mutation was found by exome sequencing and confirmed by Sanger sequencing. The patient was originally reported by Armour et al. (2009) as having spastic paraparesis, brachydactyly, and dysmorphic facial features, but Armour et al. (2016) concluded that these additional features may not have been caused by the TBL1XR1 mutation. Functional studies of the variant were not performed.


▼ REFERENCES

  1. Armour, C. M., Humphreys, P., Hennekam, R. C. M., Boycott, K. M. Fitzsimmons syndrome: spastic paraplegia, brachydactyly and cognitive impairment. Am. J. Med. Genet. 149A: 2254-2257, 2009. [PubMed: 19760657, related citations] [Full Text]

  2. Armour, C. M., Smith, A., Hartley, T., Chardon, J. W., Sawyer, S., Schwartzentruber, J., Hennekam, R., Majewski, J., Bulman, D. E., FORGE Canada Consortium, Suri, M., Boycott, K. M. Syndrome disintegration: exome sequencing reveals that Fitzsimmons syndrome is a co-occurrence of multiple events. Am. J. Med. Genet. 170A: 1820-1825, 2016. [PubMed: 27133561, related citations] [Full Text]

  3. O'Roak, B. J., Vives, L., Fu, W., Egertson, J. D., Stanaway, I. B., Phelps, I. G., Carvill, G., Kumar, A., Lee, C., Ankenman, K., Munson, J., Hiatt, J. B., and 14 others. Multiplex targeted sequencing identifies recurrently mutated genes in autism spectrum disorders. Science 338: 1619-1622, 2012. [PubMed: 23160955, images, related citations] [Full Text]

  4. O'Roak, B. J., Vives, L., Girirajan, S., Karakoc, E., Krumm, N., Coe, B. P., Levy, R., Ko, A., Lee, C., Smith, J. D., Turner, E. H., Stanaway, I. B., and 11 others. Sporadic autism exomes reveal a highly interconnected protein network of de novo mutations. Nature 485: 246-250, 2012. [PubMed: 22495309, images, related citations] [Full Text]

  5. Pons, L., Cordier, M. P., Labalme, A., Till, M., Louvrier, C., Schluth-Bolard, C., Lesca, G., Edery, P., Sanlaville, D. A new syndrome of intellectual disability with dysmorphism due to TBL1XR1 deletion. Am. J. Med. Genet. 167A: 164-168, 2015. [PubMed: 25425123, related citations] [Full Text]

  6. Saitsu, H., Tohyama, J., Walsh, T., Kato, M., Kobayashi, Y., Lee, M., Tsurusaki, Y., Miyake, N., Goto, Y., Nishino, I., Ohtake, A., King, M.-C., Matsumoto, N. A girl with West syndrome and autistic features harboring a de novo TBL1XR1 mutation. J. Hum. Genet. 59: 581-583, 2014. [PubMed: 25102098, related citations] [Full Text]

  7. Tabet, A.-C., Leroy, C., Dupont, C., Serrano, E., Hernandez, K., Gallard, J., Pouvreau, N., Gadisseux, J.-F., Benzacken, B., Verloes, A. De novo deletion of TBL1XR1 in a child with non-specific developmental delay supports its implication in intellectual disability. Am. J. Med. Genet. 164A: 2335-2337, 2014. [PubMed: 24891185, related citations] [Full Text]


Creation Date:
Cassandra L. Kniffin : 5/10/2016
Edit History:
alopez : 04/20/2022
carol : 02/20/2020
carol : 06/22/2016
carol : 5/11/2016
ckniffin : 5/10/2016

# 616944

INTELLECTUAL DEVELOPMENTAL DISORDER, AUTOSOMAL DOMINANT 41; MRD41


Alternative titles; symbols

MENTAL RETARDATION, AUTOSOMAL DOMINANT 41


DO: 0070071;  


Phenotype-Gene Relationships

Location Phenotype Phenotype
MIM number 		Inheritance Phenotype
mapping key 		Gene/Locus Gene/Locus
MIM number
3q26.32 Intellectual developmental disorder, autosomal dominant 41 616944 Autosomal dominant 3 TBL1XR1 608628

TEXT

A number sign (#) is used with this entry because of evidence that autosomal dominant intellectual developmental disorder-41 (MRD41) is caused by heterozygous mutation in the TBL1XR1 gene (608628) on chromosome 3q26.

Clinical Features

Saitsu et al. (2014) reported a 5-year-old Japanese girl with intellectual disability and autistic features. She developed infantile spasms at age 5 months. Electroencephalogram (EEG) later showed hypsarrhythmia and brain MRI revealed no structural brain anomalies; these features were consistent with a clinical diagnosis of West syndrome. She had no eye fixation or pursuit at age 7 months and had mild dysmorphic features. At age 8 months, she developed stereotypic hand movements; at age 5 years, she could walk with support, had a developmental quotient of 13, and showed autistic features.

Clinical Variability

Armour et al. (2009) reported a 15-year-old boy with global developmental delay, early-onset spastic paraparesis with increased lower limb muscle tone and bilateral extensor plantar responses, and dysfunctional bladder voiding with nocturnal enuresis. Physical examination at age 15 years showed microcephaly and small hands and feet with marked brachydactyly, particularly of the second and fifth fingers. Thumbs and big toes were short and broad, and radiographs showed short metacarpals and phalanges. He had a long oval face, facial asymmetry, small chin, dysarthria with hypernasal speech, and high-arched palate. One radiograph available from childhood showed cone-shaped epiphysis of the proximal phalanx of the right great toe. The patient also had Tourette syndrome (137580), which was also present in his otherwise unaffected brother. Karyotype and chromosomal microarray analyses were normal. Armour et al. (2016) concluded that the additional features in this patient may not have been caused by his TBL1XR1 mutation; see MOLECULAR GENETICS.


Cytogenetics

Tabet et al. (2014) reported a 6-year-old girl with nonspecific mild to moderate intellectual disability associated with a de novo heterozygous 1.6-Mb deletion on chromosome 3q26.31-q26.32 involving the TBL1XR1 gene and predicted to result in haploinsufficiency. Brain MRI and EEG were normal, and she did not have autistic features.

Pons et al. (2015) reported an 8-year-old girl and her mother who had the same 708-kb interstitial deletion on chromosome 3q26.32 encompassing only the TBL1XR1 gene; the deletion occurred de novo in the mother. Both individuals had mild to moderate intellectual disability, speech delay, and dysmorphic facial features, including synophrys, mild hypotelorism, depression of the nasal bridge, short nose with anteverted nares, long philtrum, pointed chin, low-set ears, and dental crowding. Clinodactyly and sandal gap were also noted. Autistic features were not present.


Molecular Genetics

In a 5-year-old Japanese girl with MRD41, Saitsu et al. (2014) identified a de novo heterozygous missense mutation in the TBL1XR1 gene (G70D; 608628.0001). The mutation was found by whole-exome sequencing. Functional studies of the variant were not performed.

In a girl with MRD41 and autistic features, O'Roak et al. (2012) identified a de novo heterozygous missense mutation in the TBL1XR1 gene (L282P; 608628.0002). The patient had a nonverbal IQ of 47. Functional studies of the variant were not performed. The patient was from a cohort of 209 parent-child trios exhibiting sporadic autism spectrum disorders who underwent whole-exome sequencing. The same patient was also reported by O'Roak et al. (2012).

In a boy with MRD41 and autistic features, O'Roak et al. (2012) identified a de novo heterozygous truncating mutation in the TBL1XR1 gene (608628.0003). Functional studies of the variant were not performed. The patient was from a cohort of 2,446 autism spectrum disorder probands who underwent sequencing of 44 candidate genes.

In a patient with MRD41, Armour et al. (2016) identified a de novo heterozygous missense mutation in the TBL1XR1 gene (Y245C; 608628.0004). The mutation was found by exome sequencing and confirmed by Sanger sequencing. The patient was originally reported by Armour et al. (2009) as having spastic paraparesis, brachydactyly, and dysmorphic facial features, but Armour et al. (2016) concluded that these additional features may not have been caused by the TBL1XR1 mutation. Functional studies of the variant were not performed.


REFERENCES

  1. Armour, C. M., Humphreys, P., Hennekam, R. C. M., Boycott, K. M. Fitzsimmons syndrome: spastic paraplegia, brachydactyly and cognitive impairment. Am. J. Med. Genet. 149A: 2254-2257, 2009. [PubMed: 19760657] [Full Text: https://doi.org/10.1002/ajmg.a.33003]

  2. Armour, C. M., Smith, A., Hartley, T., Chardon, J. W., Sawyer, S., Schwartzentruber, J., Hennekam, R., Majewski, J., Bulman, D. E., FORGE Canada Consortium, Suri, M., Boycott, K. M. Syndrome disintegration: exome sequencing reveals that Fitzsimmons syndrome is a co-occurrence of multiple events. Am. J. Med. Genet. 170A: 1820-1825, 2016. [PubMed: 27133561] [Full Text: https://doi.org/10.1002/ajmg.a.37684]

  3. O'Roak, B. J., Vives, L., Fu, W., Egertson, J. D., Stanaway, I. B., Phelps, I. G., Carvill, G., Kumar, A., Lee, C., Ankenman, K., Munson, J., Hiatt, J. B., and 14 others. Multiplex targeted sequencing identifies recurrently mutated genes in autism spectrum disorders. Science 338: 1619-1622, 2012. [PubMed: 23160955] [Full Text: https://doi.org/10.1126/science.1227764]

  4. O'Roak, B. J., Vives, L., Girirajan, S., Karakoc, E., Krumm, N., Coe, B. P., Levy, R., Ko, A., Lee, C., Smith, J. D., Turner, E. H., Stanaway, I. B., and 11 others. Sporadic autism exomes reveal a highly interconnected protein network of de novo mutations. Nature 485: 246-250, 2012. [PubMed: 22495309] [Full Text: https://doi.org/10.1038/nature10989]

  5. Pons, L., Cordier, M. P., Labalme, A., Till, M., Louvrier, C., Schluth-Bolard, C., Lesca, G., Edery, P., Sanlaville, D. A new syndrome of intellectual disability with dysmorphism due to TBL1XR1 deletion. Am. J. Med. Genet. 167A: 164-168, 2015. [PubMed: 25425123] [Full Text: https://doi.org/10.1002/ajmg.a.36759]

  6. Saitsu, H., Tohyama, J., Walsh, T., Kato, M., Kobayashi, Y., Lee, M., Tsurusaki, Y., Miyake, N., Goto, Y., Nishino, I., Ohtake, A., King, M.-C., Matsumoto, N. A girl with West syndrome and autistic features harboring a de novo TBL1XR1 mutation. J. Hum. Genet. 59: 581-583, 2014. [PubMed: 25102098] [Full Text: https://doi.org/10.1038/jhg.2014.71]

  7. Tabet, A.-C., Leroy, C., Dupont, C., Serrano, E., Hernandez, K., Gallard, J., Pouvreau, N., Gadisseux, J.-F., Benzacken, B., Verloes, A. De novo deletion of TBL1XR1 in a child with non-specific developmental delay supports its implication in intellectual disability. Am. J. Med. Genet. 164A: 2335-2337, 2014. [PubMed: 24891185] [Full Text: https://doi.org/10.1002/ajmg.a.36619]


Creation Date:
Cassandra L. Kniffin : 5/10/2016

Edit History:
alopez : 04/20/2022
carol : 02/20/2020
carol : 06/22/2016
carol : 5/11/2016
ckniffin : 5/10/2016



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OMIM® and Online Mendelian Inheritance in Man® are registered trademarks of the Johns Hopkins University.
Copyright® 1966-2024 Johns Hopkins University.

NOTE: OMIM is intended for use primarily by physicians and other professionals concerned with genetic disorders, by genetics researchers, and by advanced students in science and medicine. While the OMIM database is open to the public, users seeking information about a personal medical or genetic condition are urged to consult with a qualified physician for diagnosis and for answers to personal questions.
OMIM® and Online Mendelian Inheritance in Man® are registered trademarks of the Johns Hopkins University.
Copyright® 1966-2024 Johns Hopkins University.
Printed: June 5, 2024