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Intellectual developmental disorder, autosomal dominant 64(MRD64)

MedGen UID:
1784554
Concept ID:
C5543067
Disease or Syndrome
Synonym: MENTAL RETARDATION, AUTOSOMAL DOMINANT 64
 
Gene (location): ZNF292 (6q14.3)
 
Monarch Initiative: MONDO:0030934
OMIM®: 619188

Definition

Autosomal dominant intellectual developmental disorder-64 (MRD64) is characterized by mildly to severely impaired intellectual development (ID) with speech delays. Most patients also have autism spectrum disorder (ASD). Additional features are highly variable but may include motor delay, attention deficit-hyperactivity disorder (ADHD), and nonspecific dysmorphic features (summary by Mirzaa et al., 2020). [from OMIM]

Clinical features

From HPO
Single transverse palmar crease
MedGen UID:
96108
Concept ID:
C0424731
Finding
The distal and proximal transverse palmar creases are merged into a single transverse palmar crease.
Clinodactyly of the 5th finger
MedGen UID:
340456
Concept ID:
C1850049
Congenital Abnormality
Clinodactyly refers to a bending or curvature of the fifth finger in the radial direction (i.e., towards the 4th finger).
Growth delay
MedGen UID:
99124
Concept ID:
C0456070
Pathologic Function
A deficiency or slowing down of growth pre- and postnatally.
Feeding difficulties
MedGen UID:
65429
Concept ID:
C0232466
Finding
Impaired ability to eat related to problems gathering food and getting ready to suck, chew, or swallow it.
Chronic constipation
MedGen UID:
98325
Concept ID:
C0401149
Sign or Symptom
Constipation for longer than three months with fewer than 3 bowel movements per week, straining, lumpy or hard stools, and a sensation of anorectal obstruction or incomplete defecation.
Low-set ears
MedGen UID:
65980
Concept ID:
C0239234
Congenital Abnormality
Upper insertion of the ear to the scalp below an imaginary horizontal line drawn between the inner canthi of the eye and extending posteriorly to the ear.
Cupped ear
MedGen UID:
335186
Concept ID:
C1845447
Congenital Abnormality
Laterally protruding ear that lacks antihelical folding (including absence of inferior and superior crura).
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.
Cerebellar hypoplasia
MedGen UID:
120578
Concept ID:
C0266470
Congenital Abnormality
Cerebellar hypoplasia is a descriptive term implying a cerebellum with a reduced volume, but a normal shape and is stable over time.
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.
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.
Autistic behavior
MedGen UID:
163547
Concept ID:
C0856975
Mental or Behavioral Dysfunction
Persistent deficits in social interaction and communication and interaction as well as a markedly restricted repertoire of activity and interest as well as repetitive patterns of behavior.
Attention deficit hyperactivity disorder
MedGen UID:
220387
Concept ID:
C1263846
Mental or Behavioral Dysfunction
Attention-deficit/hyperactivity disorder (ADHD) is a behavioral disorder that typically begins in childhood and is characterized by a short attention span (inattention), an inability to be calm and stay still (hyperactivity), and poor impulse control (impulsivity). Some people with ADHD have problems with only inattention or with hyperactivity and impulsivity, but most have problems related to all three features.\n\nIn people with ADHD, the characteristic behaviors are frequent and severe enough to interfere with the activities of daily living such as school, work, and relationships with others. Because of an inability to stay focused on tasks, people with inattention may be easily distracted, forgetful, avoid tasks that require sustained attention, have difficulty organizing tasks, or frequently lose items.\n\nHyperactivity is usually shown by frequent movement. Individuals with this feature often fidget or tap their foot when seated, leave their seat when it is inappropriate to do so (such as in the classroom), or talk a lot and interrupt others.\n\nImpulsivity can result in hasty actions without thought for the consequences. Individuals with poor impulse control may have difficulty waiting for their turn, deferring to others, or considering their actions before acting.\n\nIn most affected individuals, ADHD continues throughout life, but in about one-third of individuals, signs and symptoms of ADHD go away by adulthood.\n\nMore than two-thirds of all individuals with ADHD have additional conditions, including insomnia, mood or anxiety disorders, learning disorders, or substance use disorders. Affected individuals may also have autism spectrum disorder, which is characterized by impaired communication and social interaction, or Tourette syndrome, which is a disorder characterized by repetitive and involuntary movements or noises called tics.
Periventricular nodular heterotopia
MedGen UID:
358387
Concept ID:
C1868720
Disease or Syndrome
Nodules of heterotopia along the ventricular walls. There can be a single nodule or a large number of nodules, they can exist on either or both sides of the brain at any point along the higher ventricle margins, they can be small or large, single or multiple.
Ventriculomegaly
MedGen UID:
480553
Concept ID:
C3278923
Finding
An increase in size of the ventricular system of the brain.
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.
Micrognathia
MedGen UID:
44428
Concept ID:
C0025990
Congenital Abnormality
Developmental hypoplasia of the mandible.
Hypertonia
MedGen UID:
10132
Concept ID:
C0026826
Finding
A condition in which there is increased muscle tone so that arms or legs, for example, are stiff and difficult to move.
Hypotonia
MedGen UID:
10133
Concept ID:
C0026827
Finding
Hypotonia is an abnormally low muscle tone (the amount of tension or resistance to movement in a muscle). Even when relaxed, muscles have a continuous and passive partial contraction which provides some resistance to passive stretching. Hypotonia thus manifests as diminished resistance to passive stretching. Hypotonia is not the same as muscle weakness, although the two conditions can co-exist.
Prominent metopic ridge
MedGen UID:
387953
Concept ID:
C1857949
Finding
Vertical bony ridge positioned in the midline of the forehead.
Plagiocephaly
MedGen UID:
1825944
Concept ID:
C2081594
Finding
Asymmetric head shape, which is usually a combination of unilateral occipital flattening with ipsilateral frontal prominence, leading to rhomboid cranial shape.
Microcephaly
MedGen UID:
1644158
Concept ID:
C4551563
Finding
Head circumference below 2 standard deviations below the mean for age and gender.
Bulbous nose
MedGen UID:
66013
Concept ID:
C0240543
Finding
Increased volume and globular shape of the anteroinferior aspect of the nose.
High palate
MedGen UID:
66814
Concept ID:
C0240635
Congenital Abnormality
Height of the palate more than 2 SD above the mean (objective) or palatal height at the level of the first permanent molar more than twice the height of the teeth (subjective).
Upslanted palpebral fissure
MedGen UID:
98390
Concept ID:
C0423109
Finding
The palpebral fissure inclination is more than two standard deviations above the mean for age (objective); or, the inclination of the palpebral fissure is greater than typical for age.
Epicanthus
MedGen UID:
151862
Concept ID:
C0678230
Congenital Abnormality
Epicanthus is a condition in which a fold of skin stretches from the upper to the lower eyelid, partially covering the inner canthus. Usher (1935) noted that epicanthus is a normal finding in the fetus of all races. Epicanthus also occurs in association with hereditary ptosis (110100).
Smooth philtrum
MedGen UID:
222980
Concept ID:
C1142533
Finding
Flat skin surface, with no ridge formation in the central region of the upper lip between the nasal base and upper vermilion border.
Depressed nasal bridge
MedGen UID:
373112
Concept ID:
C1836542
Finding
Posterior positioning of the nasal root in relation to the overall facial profile for age.
Prominent forehead
MedGen UID:
373291
Concept ID:
C1837260
Finding
Forward prominence of the entire forehead, due to protrusion of the frontal bone.
Anteverted nares
MedGen UID:
326648
Concept ID:
C1840077
Finding
Anteriorly-facing nostrils viewed with the head in the Frankfurt horizontal and the eyes of the observer level with the eyes of the subject. This gives the appearance of an upturned nose (upturned nasal tip).
Pointed chin
MedGen UID:
336193
Concept ID:
C1844505
Finding
A marked tapering of the lower face to the chin.
Short philtrum
MedGen UID:
350006
Concept ID:
C1861324
Finding
Distance between nasal base and midline upper lip vermilion border more than 2 SD below the mean. Alternatively, an apparently decreased distance between nasal base and midline upper lip vermilion border.
Thin upper lip vermilion
MedGen UID:
355352
Concept ID:
C1865017
Finding
Height of the vermilion of the upper lip in the midline more than 2 SD below the mean. Alternatively, an apparently reduced height of the vermilion of the upper lip in the frontal view (subjective).
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.
Synophrys
MedGen UID:
98132
Concept ID:
C0431447
Congenital Abnormality
Meeting of the medial eyebrows in the midline.
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.
Hypertelorism
MedGen UID:
9373
Concept ID:
C0020534
Finding
Although hypertelorism means an excessive distance between any paired organs (e.g., the nipples), the use of the word has come to be confined to ocular hypertelorism. Hypertelorism occurs as an isolated feature and is also a feature of many syndromes, e.g., Opitz G syndrome (see 300000), Greig cephalopolysyndactyly (175700), and Noonan syndrome (163950) (summary by Cohen et al., 1995).
Nystagmus
MedGen UID:
45166
Concept ID:
C0028738
Disease or Syndrome
Rhythmic, involuntary oscillations of one or both eyes related to abnormality in fixation, conjugate gaze, or vestibular mechanisms.
Strabismus
MedGen UID:
21337
Concept ID:
C0038379
Disease or Syndrome
A misalignment of the eyes so that the visual axes deviate from bifoveal fixation. The classification of strabismus may be based on a number of features including the relative position of the eyes, whether the deviation is latent or manifest, intermittent or constant, concomitant or otherwise and according to the age of onset and the relevance of any associated refractive error.

Professional guidelines

PubMed

Valverde de Morales HG, Wang HV, Garber K, Cheng X, Corces VG, Li H
Am J Med Genet A 2023 Mar;191(3):718-729. Epub 2022 Dec 1 doi: 10.1002/ajmg.a.63065. PMID: 36454652Free PMC Article
Ng SY, Luk HM, Hau EW, Cheng SS, Yu KP, Ho S, Mok MT, Lo IF
Eur J Med Genet 2022 Oct;65(10):104573. Epub 2022 Jul 31 doi: 10.1016/j.ejmg.2022.104573. PMID: 35918040

Recent clinical studies

Etiology

Wojcik MH, Srivastava S, Agrawal PB, Balci TB, Callewaert B, Calvo PL, Carli D, Caudle M, Colaiacovo S, Cross L, Demetriou K, Drazba K, Dutra-Clarke M, Edwards M, Genetti CA, Grange DK, Hickey SE, Isidor B, Küry S, Lachman HM, Lavillaureix A, Lyons MJ, Marcelis C, Marco EJ, Martinez-Agosto JA, Nowak C, Pizzol A, Planes M, Prijoles EJ, Riberi E, Rush ET, Russell BE, Sachdev R, Schmalz B, Shears D, Stevenson DA, Wilson K, Jansen S, de Vries BBA, Curry CJ
Am J Med Genet A 2023 Jul;191(7):1900-1910. Epub 2023 May 14 doi: 10.1002/ajmg.a.63226. PMID: 37183572Free PMC Article
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
Parenti I, Lehalle D, Nava C, Torti E, Leitão E, Person R, Mizuguchi T, Matsumoto N, Kato M, Nakamura K, de Man SA, Cope H, Shashi V; Undiagnosed Diseases Network, Friedman J, Joset P, Steindl K, Rauch A, Muffels I, van Hasselt PM, Petit F, Smol T, Le Guyader G, Bilan F, Sorlin A, Vitobello A, Philippe C, van de Laar IMBH, van Slegtenhorst MA, Campeau PM, Au PYB, Nakashima M, Saitsu H, Yamamoto T, Nomura Y, Louie RJ, Lyons MJ, Dobson A, Plomp AS, Motazacker MM, Kaiser FJ, Timberlake AT, Fuchs SA, Depienne C, Mignot C
Hum Genet 2021 Jul;140(7):1109-1120. Epub 2021 May 4 doi: 10.1007/s00439-021-02283-2. PMID: 33944996Free PMC Article
Arora P, Tullu MS, Muranjan MN, Kerkar SP, Girisha KM, Bharucha BA
Indian J Pediatr 2003 Jul;70(7):549-52. doi: 10.1007/BF02723156. PMID: 12940376
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

Diagnosis

Wojcik MH, Srivastava S, Agrawal PB, Balci TB, Callewaert B, Calvo PL, Carli D, Caudle M, Colaiacovo S, Cross L, Demetriou K, Drazba K, Dutra-Clarke M, Edwards M, Genetti CA, Grange DK, Hickey SE, Isidor B, Küry S, Lachman HM, Lavillaureix A, Lyons MJ, Marcelis C, Marco EJ, Martinez-Agosto JA, Nowak C, Pizzol A, Planes M, Prijoles EJ, Riberi E, Rush ET, Russell BE, Sachdev R, Schmalz B, Shears D, Stevenson DA, Wilson K, Jansen S, de Vries BBA, Curry CJ
Am J Med Genet A 2023 Jul;191(7):1900-1910. Epub 2023 May 14 doi: 10.1002/ajmg.a.63226. PMID: 37183572Free PMC Article
Valverde de Morales HG, Wang HV, Garber K, Cheng X, Corces VG, Li H
Am J Med Genet A 2023 Mar;191(3):718-729. Epub 2022 Dec 1 doi: 10.1002/ajmg.a.63065. PMID: 36454652Free PMC Article
Pires LVL, Ribeiro RL, Sousa AM, Linnenkamp BDW, Pontes SE, Teixeira MCTV, Befi-Lopes DM, Honjo RS, Bertola DR, Kim CA
Arq Neuropsiquiatr 2021 Nov;79(11):950-956. doi: 10.1590/0004-282X-ANP-2020-0450. PMID: 34816986
Morlino S, Nardella G, Castellana S, Micale L, Copetti M, Fusco C, Castori M
Am J Med Genet A 2021 Mar;185(3):955-965. Epub 2020 Dec 27 doi: 10.1002/ajmg.a.62047. PMID: 33369135
Kruszka P, Addissie YA, Yarnell CM, Hadley DW, Guillen Sacoto MJ, Platte P, Paelecke Y, Collmann H, Snow N, Schweitzer T, Boyadjiev SA, Aravidis C, Hall SE, Mulliken JB, Roscioli T, Muenke M
Am J Med Genet A 2016 Apr;170A(4):918-29. Epub 2016 Jan 6 doi: 10.1002/ajmg.a.37528. PMID: 26740388

Therapy

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
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

Prognosis

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
Morlino S, Nardella G, Castellana S, Micale L, Copetti M, Fusco C, Castori M
Am J Med Genet A 2021 Mar;185(3):955-965. Epub 2020 Dec 27 doi: 10.1002/ajmg.a.62047. PMID: 33369135
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
Paganini L, Pesenti C, Milani D, Fontana L, Motta S, Sirchia SM, Scuvera G, Marchisio P, Esposito S, Cinnante CM, Tabano SM, Miozzo MR
Am J Med Genet A 2018 Jun;176(6):1427-1431. Epub 2018 Apr 16 doi: 10.1002/ajmg.a.38704. PMID: 29663667
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

Ng SY, Luk HM, Hau EW, Cheng SS, Yu KP, Ho S, Mok MT, Lo IF
Eur J Med Genet 2022 Oct;65(10):104573. Epub 2022 Jul 31 doi: 10.1016/j.ejmg.2022.104573. PMID: 35918040
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
Parenti I, Lehalle D, Nava C, Torti E, Leitão E, Person R, Mizuguchi T, Matsumoto N, Kato M, Nakamura K, de Man SA, Cope H, Shashi V; Undiagnosed Diseases Network, Friedman J, Joset P, Steindl K, Rauch A, Muffels I, van Hasselt PM, Petit F, Smol T, Le Guyader G, Bilan F, Sorlin A, Vitobello A, Philippe C, van de Laar IMBH, van Slegtenhorst MA, Campeau PM, Au PYB, Nakashima M, Saitsu H, Yamamoto T, Nomura Y, Louie RJ, Lyons MJ, Dobson A, Plomp AS, Motazacker MM, Kaiser FJ, Timberlake AT, Fuchs SA, Depienne C, Mignot C
Hum Genet 2021 Jul;140(7):1109-1120. Epub 2021 May 4 doi: 10.1007/s00439-021-02283-2. PMID: 33944996Free PMC Article
Morlino S, Nardella G, Castellana S, Micale L, Copetti M, Fusco C, Castori M
Am J Med Genet A 2021 Mar;185(3):955-965. Epub 2020 Dec 27 doi: 10.1002/ajmg.a.62047. PMID: 33369135
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

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