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Intellectual disability, autosomal dominant 4(MRD4)

MedGen UID:: 393397
•Concept ID:: C2675487
•: Mental or Behavioral Dysfunction

Synonym:	MRD4

Monarch Initiative:	MONDO:0012947
OMIM®:	612581

Definition

Any autosomal dominant non-syndromic intellectual disability in which the cause of the disease is a mutation in the KIRREL3 gene. [from MONDO]

Clinical features

From HPO

Syndactyly

MedGen UID:: 52619
•Concept ID:: C0039075
•: Congenital Abnormality

Webbing or fusion of the fingers or toes, involving soft parts only or including bone structure. Bony fusions are referred to as "bony" syndactyly if the fusion occurs in a radio-ulnar axis. Fusions of bones of the fingers or toes in a proximo-distal axis are referred to as "symphalangism".

See: Feature record | Search on this feature

Short toe

MedGen UID:: 322858
•Concept ID:: C1836195
•: Finding

A toe that appears disproportionately short compared to the foot.

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Intellectual disability, severe

MedGen UID:: 48638
•Concept ID:: C0036857
•: Mental or Behavioral Dysfunction

Severe mental retardation is defined as an intelligence quotient (IQ) in the range of 20-34.

See: Feature record | Search on this feature

Intellectual disability

MedGen UID:: 811461
•Concept ID:: C3714756
•: Mental or Behavioral Dysfunction

Intellectual disability, previously referred to as mental retardation, is characterized by subnormal intellectual functioning that occurs during the developmental period. It is defined by an IQ score below 70.

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Midface retrusion

MedGen UID:: 339938
•Concept ID:: C1853242
•: Anatomical Abnormality

Posterior positions and/or vertical shortening of the infraorbital and perialar regions, or increased concavity of the face and/or reduced nasolabial angle.

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Short chin

MedGen UID:: 784514
•Concept ID:: C3697248
•: Finding

Decreased vertical distance from the vermilion border of the lower lip to the inferior-most point of the chin.

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Exotropia

MedGen UID:: 4613
•Concept ID:: C0015310
•: Disease or Syndrome

A form of strabismus with one or both eyes deviated outward.

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Abnormality of head or neck
- Midface retrusion
- Short chin
Abnormality of limbs
- Short toe
- Syndactyly
Abnormality of the eye
- Exotropia
Abnormality of the nervous system
- Intellectual disability
- Intellectual disability, severe

Professional guidelines

PubMed

Updated Genotype-Phenotype Correlations in TSC.

Curatolo P, Trivisano M, Specchio N
Semin Pediatr Neurol 2023 Oct;47:101086. Epub 2023 Sep 18 doi: 10.1016/j.spen.2023.101086. PMID: 37919037

Genotype/Phenotype Correlations in Tuberous Sclerosis Complex.

Curatolo P, Moavero R, Roberto D, Graziola F
Semin Pediatr Neurol 2015 Dec;22(4):259-73. Epub 2015 Oct 21 doi: 10.1016/j.spen.2015.10.002. PMID: 26706013

Rubinstein-Taybi syndrome: clinical features, genetic basis, diagnosis, and management.

Milani D, Manzoni FM, Pezzani L, Ajmone P, Gervasini C, Menni F, Esposito S
Ital J Pediatr 2015 Jan 20;41:4. doi: 10.1186/s13052-015-0110-1. PMID: 25599811 Free PMC Article

See all (8)

Recent clinical studies

Etiology

Updated Genotype-Phenotype Correlations in TSC.

Curatolo P, Trivisano M, Specchio N
Semin Pediatr Neurol 2023 Oct;47:101086. Epub 2023 Sep 18 doi: 10.1016/j.spen.2023.101086. PMID: 37919037

Dermatological findings in Rubinstein-Taybi Syndrome.

Cammarata-Scalisi F, Diociaiuti A, Cárdenas Tadich A, Sandoval X, Oranges T, Filippeschi C, Araya Castillo M, Willoughby CE, Cerri A, Gervasini C, Callea M
Ital J Dermatol Venerol 2023 Aug;158(4):316-320. Epub 2023 Jun 7 doi: 10.23736/S2784-8671.23.07547-3. PMID: 37282850

Clinical experience with non-invasive prenatal screening for single-gene disorders.

Mohan P, Lemoine J, Trotter C, Rakova I, Billings P, Peacock S, Kao CY, Wang Y, Xia F, Eng CM, Benn P
Ultrasound Obstet Gynecol 2022 Jan;59(1):33-39. doi: 10.1002/uog.23756. PMID: 34358384 Free PMC Article

TCF4, schizophrenia, and Pitt-Hopkins Syndrome.

Blake DJ, Forrest M, Chapman RM, Tinsley CL, O'Donovan MC, Owen MJ
Schizophr Bull 2010 May;36(3):443-7. Epub 2010 Apr 26 doi: 10.1093/schbul/sbq035. PMID: 20421335 Free PMC Article

Genetics of retinoblastoma.

Vogel F
Hum Genet 1979 Nov 1;52(1):1-54. doi: 10.1007/BF00284597. PMID: 393614

See all (79)

Diagnosis

Updated Genotype-Phenotype Correlations in TSC.

Curatolo P, Trivisano M, Specchio N
Semin Pediatr Neurol 2023 Oct;47:101086. Epub 2023 Sep 18 doi: 10.1016/j.spen.2023.101086. PMID: 37919037

Dermatological findings in Rubinstein-Taybi Syndrome.

Clinical experience with non-invasive prenatal screening for single-gene disorders.

Generation of 10 patient-specific induced pluripotent stem cells (iPSCs) to model Pitt-Hopkins Syndrome.

Sripathy SR, Wang Y, Moses RL, Fatemi A, Batista DA, Maher BJ
Stem Cell Res 2020 Oct;48:102001. Epub 2020 Sep 17 doi: 10.1016/j.scr.2020.102001. PMID: 32971458 Free PMC Article

TCF4, schizophrenia, and Pitt-Hopkins Syndrome.

Blake DJ, Forrest M, Chapman RM, Tinsley CL, O'Donovan MC, Owen MJ
Schizophr Bull 2010 May;36(3):443-7. Epub 2010 Apr 26 doi: 10.1093/schbul/sbq035. PMID: 20421335 Free PMC Article

See all (121)

Therapy

Clinical and functional studies of MTOR variants in Smith-Kingsmore syndrome reveal deficits of circadian rhythm and sleep-wake behavior.

Liu AC, Shen Y, Serbinski CR, He H, Roman D, Endale M, Aschbacher-Smith L, King KA, Granadillo JL, López I, Krueger DA, Dye TJ, Smith DF, Hogenesch JB, Prada CE
HGG Adv 2024 Oct 10;5(4):100333. Epub 2024 Jul 17 doi: 10.1016/j.xhgg.2024.100333. PMID: 39030910 Free PMC Article

Association of Alzheimer Disease With Life Expectancy in People With Down Syndrome.

Iulita MF, Garzón Chavez D, Klitgaard Christensen M, Valle Tamayo N, Plana-Ripoll O, Rasmussen SA, Roqué Figuls M, Alcolea D, Videla L, Barroeta I, Benejam B, Altuna M, Padilla C, Pegueroles J, Fernandez S, Belbin O, Carmona-Iragui M, Blesa R, Lleó A, Bejanin A, Fortea J
JAMA Netw Open 2022 May 2;5(5):e2212910. doi: 10.1001/jamanetworkopen.2022.12910. PMID: 35604690 Free PMC Article

Court orders on procreation.

Matevosyan NR
Arch Gynecol Obstet 2016 Jan;293(1):87-99. Epub 2015 Jun 11 doi: 10.1007/s00404-015-3770-6. PMID: 26063342

Autosomal dominant type I osteopetrosis is related with iatrogenic fractures in arthroplasty.

van Hove RP, de Jong T, Nolte PA
Clin Orthop Surg 2014 Dec;6(4):484-8. Epub 2014 Nov 10 doi: 10.4055/cios.2014.6.4.484. PMID: 25436076 Free PMC Article

Paternal contributions to birth defects.

Cohen FL
Nurs Clin North Am 1986 Mar;21(1):49-64. PMID: 2937020

See all (11)

Prognosis

A deep intronic DLG4 variant resulting in DLG4-related synaptopathy.

Levy AM, Ganapathi M, Chung WK, Tümer Z
Clin Genet 2024 Jan;105(1):77-80. Epub 2023 Aug 1 doi: 10.1111/cge.14411. PMID: 37525972

Updated Genotype-Phenotype Correlations in TSC.

Curatolo P, Trivisano M, Specchio N
Semin Pediatr Neurol 2023 Oct;47:101086. Epub 2023 Sep 18 doi: 10.1016/j.spen.2023.101086. PMID: 37919037

Parkinson's disease - genetic cause.

Cherian A, K P D, Vijayaraghavan A
Curr Opin Neurol 2023 Aug 1;36(4):292-301. Epub 2023 May 24 doi: 10.1097/WCO.0000000000001167. PMID: 37366140

De novo heterozygous missense and loss-of-function variants in CDC42BPB are associated with a neurodevelopmental phenotype.

Chilton I, Okur V, Vitiello G, Selicorni A, Mariani M, Goldenberg A, Husson T, Campion D, Lichtenbelt KD, van Gassen K, Steinraths M, Rice J, Roeder ER, Littlejohn RO, Srour M, Sebire G, Accogli A, Héron D, Heide S, Nava C, Depienne C, Larson A, Niyazov D, Azage M, Hoganson G, Burton J, Rush ET, Jenkins JL, Saunders CJ, Thiffault I, Alaimo JT, Fleischer J, Groepper D, Gripp KW, Chung WK
Am J Med Genet A 2020 May;182(5):962-973. Epub 2020 Feb 7 doi: 10.1002/ajmg.a.61505. PMID: 32031333

Dominant LMAN2L mutation causes intellectual disability with remitting epilepsy.

Alkhater RA, Wang P, Ruggieri A, Israelian L, Walker S, Scherer SW, Smith ML, Minassian BA
Ann Clin Transl Neurol 2019 Apr;6(4):807-811. Epub 2019 Mar 7 doi: 10.1002/acn3.727. PMID: 31020005 Free PMC Article

See all (42)

Clinical prediction guides

A deep intronic DLG4 variant resulting in DLG4-related synaptopathy.

Levy AM, Ganapathi M, Chung WK, Tümer Z
Clin Genet 2024 Jan;105(1):77-80. Epub 2023 Aug 1 doi: 10.1111/cge.14411. PMID: 37525972

Updated Genotype-Phenotype Correlations in TSC.

Curatolo P, Trivisano M, Specchio N
Semin Pediatr Neurol 2023 Oct;47:101086. Epub 2023 Sep 18 doi: 10.1016/j.spen.2023.101086. PMID: 37919037

Parkinson's disease - genetic cause.

Cherian A, K P D, Vijayaraghavan A
Curr Opin Neurol 2023 Aug 1;36(4):292-301. Epub 2023 May 24 doi: 10.1097/WCO.0000000000001167. PMID: 37366140

Clinical experience with non-invasive prenatal screening for single-gene disorders.

De novo heterozygous missense and loss-of-function variants in CDC42BPB are associated with a neurodevelopmental phenotype.

See all (77)

Recent systematic reviews

Autosomal Recessive Guanosine Triphosphate Cyclohydrolase I Deficiency: Redefining the Phenotypic Spectrum and Outcomes.

Novelli M, Tolve M, Quiroz V, Carducci C, Bove R, Ricciardi G, Yang K, Manti F, Pisani F, Ebrahimi-Fakhari D, Galosi S, Leuzzi V
Mov Disord Clin Pract 2024 Sep;11(9):1072-1084. Epub 2024 Jul 12 doi: 10.1002/mdc3.14157. PMID: 39001623 Free PMC Article

Ophthalmologic and facial abnormalities of Nicolaides-Baraitser syndrome.

Simmers R, Goodwin A, Al Saif H, Couser N
Ophthalmic Genet 2022 Oct;43(5):699-702. Epub 2022 Jun 27 doi: 10.1080/13816810.2022.2089358. PMID: 35762114

See all (2)

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Intellectual disability, autosomal dominant 4(MRD4)

Definition

Clinical features

Professional guidelines

PubMed

Recent clinical studies

Etiology

Diagnosis

Therapy

Prognosis

Clinical prediction guides

Recent systematic reviews

Supplemental Content

Table of contents

Genetic Testing Registry

Clinical resources

Practice guidelines

Molecular resources

Consumer resources

Reviews

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