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Intellectual disability, autosomal dominant 2(MRD2)

MedGen UID:
481472
•Concept ID:
C3279842
•
Mental or Behavioral Dysfunction
Synonym: MRD2
 
Monarch Initiative: MONDO:0013581
OMIM®: 614113

Definition

Any autosomal dominant non-syndromic intellectual disability in which the cause of the disease is a mutation in the DOCK8 gene. [from MONDO]

Clinical features

From HPO
Cholesteatoma
MedGen UID:
3043
•Concept ID:
C0008373
•
Disease or Syndrome
Cholesteatoma is a benign but potentially destructive growth consisting of keratinizing epithelium located in the middle ear and/or mastoid process. In cholesteatoma, a skin cyst grows into the middle ear and mastoid. The cyst is not cancerous but can erode tissue and cause destruction of the ear.
See: Feature record | Search on this feature
Seizure
MedGen UID:
20693
•Concept ID:
C0036572
•
Sign or Symptom
A seizure is an intermittent abnormality of nervous system physiology characterized by a transient occurrence of signs and/or symptoms due to abnormal excessive or synchronous neuronal activity in the brain.
See: Feature record | Search on this feature
Delayed speech and language development
MedGen UID:
105318
•Concept ID:
C0454644
•
Finding
A degree of language development that is significantly below the norm for a child of a specified age.
See: Feature record | Search on this feature
Global developmental delay
MedGen UID:
107838
•Concept ID:
C0557874
•
Finding
A delay in the achievement of motor or mental milestones in the domains of development of a child, including motor skills, speech and language, cognitive skills, and social and emotional skills. This term should only be used to describe children younger than five years of age.
See: Feature record | Search on this feature
Absent speech
MedGen UID:
340737
•Concept ID:
C1854882
•
Finding
Complete lack of development of speech and language abilities.
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.
See: Feature record | Search on this feature
Prominent supraorbital ridges
MedGen UID:
333982
•Concept ID:
C1842060
•
Finding
Greater than average forward and/or lateral protrusion of the supraorbital portion of the frontal bones.
See: Feature record | Search on this feature
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.
See: Feature record | Search on this feature
Prominent fingertip pads
MedGen UID:
322758
•Concept ID:
C1835807
•
Finding
A soft tissue prominence of the ventral aspects of the fingertips. The term "persistent fetal fingertip pads" is often used as a synonym, but should better not be used because it implies knowledge of history of the patient which often does not exist.
See: Feature record | Search on this feature
Deeply set eye
MedGen UID:
473112
•Concept ID:
C0423224
•
Finding
An eye that is more deeply recessed into the plane of the face than is typical.
See: Feature record | Search on this feature
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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 correlation in contactin-associated protein-like 2 (CNTNAP-2) developmental disorder.
D'Onofrio G, Accogli A, Severino M, Caliskan H, Kokotović T, Blazekovic A, Jercic KG, Markovic S, Zigman T, Goran K, Barišić N, Duranovic V, Ban A, Borovecki F, Ramadža DP, Barić I, Fazeli W, Herkenrath P, Marini C, Vittorini R, Gowda V, Bouman A, Rocca C, Alkhawaja IA, Murtaza BN, Rehman MMU, Al Alam C, Nader G, Mancardi MM, Giacomini T, Srivastava S, Alvi JR, Tomoum H, Matricardi S, Iacomino M, Riva A, Scala M, Madia F, Pistorio A, Salpietro V, Minetti C, Rivière JB, Srour M, Efthymiou S, Maroofian R, Houlden H, Vernes SC, Zara F, Striano P, Nagy V
Hum Genet 2023 Jul;142(7):909-925. Epub 2023 May 14 doi: 10.1007/s00439-023-02552-2. PMID: 37183190Free PMC Article
Diagnosis and genotype-phenotype correlation in patients with PKD1/TSC2 contiguous gene deletion syndrome.
Shang S, Mei Y, Wang T, Zheng X, Chen K, Xiong S, Dong Y, Chang Y, Wu X, Kong X, Tan M, Wu L, Zhang Y, Xiao Y, Xie Y, Cai G, Chen X, Li Q
Clin Nephrol 2022 Jun;97(6):328-338. doi: 10.5414/CN110476. PMID: 35142283

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
Clinical heterogeneity of polish patients with KAT6B-related disorder.
Klaniewska M, Bolanowska-Tyszko A, Latos-Bielenska A, Jezela-Stanek A, Szczaluba K, Krajewska-Walasek M, Ciara E, Pelc M, Jurkiewicz D, Stawinski P, Zubkiewicz-Kucharska A, Rydzanicz M, Ploski R, Smigiel R
Mol Genet Genomic Med 2023 Dec;11(12):e2265. Epub 2023 Sep 1 doi: 10.1002/mgg3.2265. PMID: 37658610Free PMC Article
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: 34358384Free PMC Article
Comprehensive mutation analysis of TSC1 and TSC2-and phenotypic correlations in 150 families with tuberous sclerosis.
Jones AC, Shyamsundar MM, Thomas MW, Maynard J, Idziaszczyk S, Tomkins S, Sampson JR, Cheadle JP
Am J Hum Genet 1999 May;64(5):1305-15. doi: 10.1086/302381. PMID: 10205261Free PMC Article
Etiology and recurrence risk in Rubinstein-Taybi syndrome.
Hennekam RC, Stevens CA, Van de Kamp JJ
Am J Med Genet Suppl 1990;6:56-64. doi: 10.1002/ajmg.1320370610. PMID: 2118780

Diagnosis

ITSN1: a novel candidate gene involved in autosomal dominant neurodevelopmental disorder spectrum.
Bruel AL, Vitobello A, Thiffault I, Manwaring L, Willing M, Agrawal PB, Bayat A, Kitzler TM, Brownstein CA, Genetti CA, Gonzalez-Heydrich J, Jayakar P, Zyskind JW, Zhu Z, Vachet C, Wilson GR, Pruniski B, Goyette AM, Duffourd Y, Thauvin-Robinet C, Philippe C, Faivre L
Eur J Hum Genet 2022 Jan;30(1):111-116. Epub 2021 Oct 28 doi: 10.1038/s41431-021-00985-9. PMID: 34707297Free PMC Article
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: 34358384Free PMC Article
Spectrum of neuro-genetic disorders in the United Arab Emirates national population.
Saleh S, Beyyumi E, Al Kaabi A, Hertecant J, Barakat D, Al Dhaheri NS, Al-Gazali L, Al Shamsi A
Clin Genet 2021 Nov;100(5):573-600. Epub 2021 Aug 19 doi: 10.1111/cge.14044. PMID: 34374989
Tuberous sclerosis: a review of the past, present, and future.
Uysal SP, Şahin M
Turk J Med Sci 2020 Nov 3;50(SI-2):1665-1676. doi: 10.3906/sag-2002-133. PMID: 32222129Free PMC Article
Posterior helical pits.
Prescott TE, Hennekam RC
Eur J Med Genet 2007 Mar-Apr;50(2):159-61. Epub 2006 Nov 30 doi: 10.1016/j.ejmg.2006.11.003. PMID: 17223397

Therapy

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: 35604690Free PMC Article
Early-onset parkinsonism in PPP2R5D-related neurodevelopmental disorder.
Hetzelt KLML, Kerling F, Kraus C, Rauch C, Thiel CT, Winterholler M, Reis A, Zweier C
Eur J Med Genet 2021 Jan;64(1):104123. Epub 2020 Dec 15 doi: 10.1016/j.ejmg.2020.104123. PMID: 33338668
Clinical and biomarker changes of Alzheimer's disease in adults with Down syndrome: a cross-sectional study.
Fortea J, Vilaplana E, Carmona-Iragui M, Benejam B, Videla L, Barroeta I, Fernández S, Altuna M, Pegueroles J, Montal V, Valldeneu S, Giménez S, González-Ortiz S, Muñoz L, Estellés T, Illán-Gala I, Belbin O, Camacho V, Wilson LR, Annus T, Osorio RS, Videla S, Lehmann S, Holland AJ, Alcolea D, Clarimón J, Zaman SH, Blesa R, Lleó A
Lancet 2020 Jun 27;395(10242):1988-1997. doi: 10.1016/S0140-6736(20)30689-9. PMID: 32593336Free PMC Article
Autism in siblings with autosomal dominant nocturnal frontal lobe epilepsy.
Miyajima T, Kumada T, Saito K, Fujii T
Brain Dev 2013 Feb;35(2):155-7. Epub 2012 Aug 9 doi: 10.1016/j.braindev.2012.07.012. PMID: 22883468
From genes to cognition in tuberous sclerosis: implications for mTOR inhibitor-based treatment approaches.
Ehninger D
Neuropharmacology 2013 May;68:97-105. Epub 2012 May 22 doi: 10.1016/j.neuropharm.2012.05.015. PMID: 22626986

Prognosis

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
The clinical and genetic spectrum of autosomal-recessive TOR1A-related disorders.
Saffari A, Lau T, Tajsharghi H, Karimiani EG, Kariminejad A, Efthymiou S, Zifarelli G, Sultan T, Toosi MB, Sedighzadeh S, Siu VM, Ortigoza-Escobar JD, AlShamsi AM, Ibrahim S, Al-Sannaa NA, Al-Hertani W, Sandra W, Tarnopolsky M, Alavi S, Li C, Day-Salvatore DL, Martínez-González MJ, Levandoski KM, Bedoukian E, Madan-Khetarpal S, Idleburg MJ, Menezes MJ, Siddharth A, Platzer K, Oppermann H, Smitka M, Collins F, Lek M, Shahrooei M, Ghavideldarestani M, Herman I, Rendu J, Faure J, Baker J, Bhambhani V, Calderwood L, Akhondian J, Imannezhad S, Mirzadeh HS, Hashemi N, Doosti M, Safi M, Ahangari N, Torbati PN, Abedini S, Salpietro V, Gulec EY, Eshaghian S, Ghazavi M, Pascher MT, Vogel M, Abicht A, Moutton S, Bruel AL, Rieubland C, Gallati S, Strom TM, Lochmüller H, Mohammadi MH, Alvi JR, Zackai EH, Keena BA, Skraban CM, Berger SI, Andrew EH, Rahimian E, Morrow MM, Wentzensen IM, Millan F, Henderson LB, Dafsari HS, Jungbluth H, Gomez-Ospina N, McRae A, Peter M, Veltra D, Marinakis NM, Sofocleous C, Ashrafzadeh F, Pehlivan D, Lemke JR, Melki J, Benezit A, Bauer P, Weis D, Lupski JR, Senderek J, Christodoulou J, Chung WK, Goodchild R, Offiah AC, Moreno-De-Luca A, Suri M, Ebrahimi-Fakhari D, Houlden H, Maroofian R
Brain 2023 Aug 1;146(8):3273-3288. doi: 10.1093/brain/awad039. PMID: 36757831Free PMC Article
Clinical and biomarker changes of Alzheimer's disease in adults with Down syndrome: a cross-sectional study.
Fortea J, Vilaplana E, Carmona-Iragui M, Benejam B, Videla L, Barroeta I, Fernández S, Altuna M, Pegueroles J, Montal V, Valldeneu S, Giménez S, González-Ortiz S, Muñoz L, Estellés T, Illán-Gala I, Belbin O, Camacho V, Wilson LR, Annus T, Osorio RS, Videla S, Lehmann S, Holland AJ, Alcolea D, Clarimón J, Zaman SH, Blesa R, Lleó A
Lancet 2020 Jun 27;395(10242):1988-1997. doi: 10.1016/S0140-6736(20)30689-9. PMID: 32593336Free PMC Article
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
Comprehensive mutation analysis of TSC1 and TSC2-and phenotypic correlations in 150 families with tuberous sclerosis.
Jones AC, Shyamsundar MM, Thomas MW, Maynard J, Idziaszczyk S, Tomkins S, Sampson JR, Cheadle JP
Am J Hum Genet 1999 May;64(5):1305-15. doi: 10.1086/302381. PMID: 10205261Free PMC Article

Clinical prediction guides

The clinical and genetic spectrum of autosomal-recessive TOR1A-related disorders.
Saffari A, Lau T, Tajsharghi H, Karimiani EG, Kariminejad A, Efthymiou S, Zifarelli G, Sultan T, Toosi MB, Sedighzadeh S, Siu VM, Ortigoza-Escobar JD, AlShamsi AM, Ibrahim S, Al-Sannaa NA, Al-Hertani W, Sandra W, Tarnopolsky M, Alavi S, Li C, Day-Salvatore DL, Martínez-González MJ, Levandoski KM, Bedoukian E, Madan-Khetarpal S, Idleburg MJ, Menezes MJ, Siddharth A, Platzer K, Oppermann H, Smitka M, Collins F, Lek M, Shahrooei M, Ghavideldarestani M, Herman I, Rendu J, Faure J, Baker J, Bhambhani V, Calderwood L, Akhondian J, Imannezhad S, Mirzadeh HS, Hashemi N, Doosti M, Safi M, Ahangari N, Torbati PN, Abedini S, Salpietro V, Gulec EY, Eshaghian S, Ghazavi M, Pascher MT, Vogel M, Abicht A, Moutton S, Bruel AL, Rieubland C, Gallati S, Strom TM, Lochmüller H, Mohammadi MH, Alvi JR, Zackai EH, Keena BA, Skraban CM, Berger SI, Andrew EH, Rahimian E, Morrow MM, Wentzensen IM, Millan F, Henderson LB, Dafsari HS, Jungbluth H, Gomez-Ospina N, McRae A, Peter M, Veltra D, Marinakis NM, Sofocleous C, Ashrafzadeh F, Pehlivan D, Lemke JR, Melki J, Benezit A, Bauer P, Weis D, Lupski JR, Senderek J, Christodoulou J, Chung WK, Goodchild R, Offiah AC, Moreno-De-Luca A, Suri M, Ebrahimi-Fakhari D, Houlden H, Maroofian R
Brain 2023 Aug 1;146(8):3273-3288. doi: 10.1093/brain/awad039. PMID: 36757831Free PMC Article
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: 34358384Free PMC Article
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
Posterior helical pits.
Prescott TE, Hennekam RC
Eur J Med Genet 2007 Mar-Apr;50(2):159-61. Epub 2006 Nov 30 doi: 10.1016/j.ejmg.2006.11.003. PMID: 17223397
Comprehensive mutation analysis of TSC1 and TSC2-and phenotypic correlations in 150 families with tuberous sclerosis.
Jones AC, Shyamsundar MM, Thomas MW, Maynard J, Idziaszczyk S, Tomkins S, Sampson JR, Cheadle JP
Am J Hum Genet 1999 May;64(5):1305-15. doi: 10.1086/302381. PMID: 10205261Free PMC Article

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: 39001623Free PMC Article

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