Ocular manifestations of microcephaly with or without chorioretinopathy, lymphedema or intellectual disability (MCLID) syndrome associated with mutations in KIF11.

Acta Ophthalmologica 2016

Case Series Ocular manifestations of microcephaly with or without chorioretinopathy, lymphedema or intellectual disability (MCLID) syndrome associated with mutations in KIF11 Irina Balikova,1,2 Anthony G. Robson,1,3 Graham E. Holder,1,3 Pia Ostergaard,4 Sahar Mansour5 and Anthony T. Moore1,3 1

Moorfields Eye Hospital, London, UK Free University of Brussels, Brussels, Belgium 3 UCL Institute of Ophthalmology, London, UK 4 Cardiovascular & Cell Sciences Research Institute, St George’s University of London, London, UK 5 SW Thames Regional Genetics Service, St George’s Healthcare NHS Trust, London, UK 2

ABSTRACT. Purpose: Microcephaly with or without chorioretinopathy, lymphedema or intellectual disability (MCLID) is an autosomal dominant condition. Mutations in KIF11 have been found to be causative in approximately 75% of cases. This study describes the ocular phenotype in patients with confirmed KIF11 mutations. Methods: Standard ophthalmic examination and investigation including visual acuity, refraction and fundus examination was carried out in all patients. Fundus autofluorescence imaging (FAF) was performed in three patients, and four patients underwent spectral domain optical coherence tomography (OCT). Flash electroretinography (ERG) was performed in seven patients, and five underwent additional pattern electroretinography (PERG). Results: The patients ranged in age from 2 to 10 years. Most presented with visual acuity loss. Fundus examination revealed lacunae of chorioretinal atrophy. Pigmentary macular changes and optic disc pallor were present in three of seven patients. Fundus autofluorescence demonstrated hypoautofluorescence at the macula in two of three patients. The lacunae of chorioretinal atrophy were hypoautofluorescent. The OCT showed atrophic maculae in three of four patients. Follow-up in one patient showed no deterioration of the vision over a 9-year period. The lesions appear not to be progressive on the follow-up imaging. Electrophysiology showed generalized rod and cone dysfunction and severe macular dysfunction. Inner retinal dysfunction was evident in three of seven patients. Conclusions: Patients with KIF11 mutations show a specific ocular phenotype with variable expressivity and intrafamilial variability. Macular atrophy and dysfunction have not been consistently documented before. The fundus lesions appear non-progressive. The findings assist in providing an accurate diagnosis and thus improving the management and follow-up of patients with this syndrome. Key words: chorioretinopathy – electroretinography – MCLID – MCLMR – microcephaly – paediatric retina – retinal dystrophy

Acta Ophthalmol. 2016: 94: 92–98 ª 2015 Acta Ophthalmologica Scandinavica Foundation. Published by John Wiley & Sons Ltd

doi: 10.1111/aos.12759

92

Introduction Microcephaly has been associated with three different retinal phenotypes: chorioretinopathy (Tenconi et al. 1981; Warburg & Heuer 1994), progressive rod-cone dystrophy (Atchaneeyasakul et al. 1998) and retinal folds (Jarmas et al. 1981; Young et al. 1987; Angle et al. 1994; Fryns et al. 1995). This report addresses the autosomal dominant form of microcephaly with or without chorioretinopathy, lymphedema or intellectual disability (MCLID, OMIM 152950), which is characterized by primary microcephaly, lymphedema, chorioretinal dysplasia and intellectual disability. The defective gene, KIF11 (Ostergaard et al. 2012), encodes a homotetrameric protein, EG5, that drives microtubule sliding and is involved in mitotic spindle assembly and chromosome segregation (Blangy et al. 1995). KIF11 mutations occur in ~75% of patients clinically diagnosed with MCLID. The associated chorioretinopathy occurs in approximately 60% of mutation-positive individuals (Jones et al. 2014). As KIF11 mutations have only recently been shown to underlie MCLID (Ostergaard et al. 2012), the associated phenotypic spectrum of ocular features is not fully documented. The present report describes the detailed ocular phenotype in seven individuals from six families with


Table 1. Summary of the ocular findings and type of KIF11 mutation. Patient/ Gender

BCVA RE LE (Age, years)

Refraction RE LE

P1/F

0.12 0.2 (10)

P2/F

Ocular fundus

Electrodiagnostic testing

Mutation

+2/ 3 9 165° +3.75/ 3.25 9 10°

Lacunae of chorioretinal atrophy, macular pigmentary changes

c.1804C>T

14

p.Gln602X

0.8 1.1 (6)

+6.25/ 0.5 9 5° +4.75/ 0.5 9 175°

Lacunae of chorioretinal atrophy

c.1804C>T

14

p.Gln602X

P3/M

3 1.3 (4)

+4.5/ 2.75 9 20° +6.5/ 2 9 180°

c.700C>T

7

P4/M

0.25 0.5 (7)

+4/ 1 9 180° +4.0/ 1.5 9 180°

Lacunae of chorioretinal atrophy, generalized retinal atrophy, pale discs, attenuated vessels Lacunae of chorioretinal atrophy, macular pigment mottling, attenuated vessels inferiorly

Generalized loss of rod function with evidence of inner retinal cone On-system involvement BE. PERG evidence of macular dysfunction, worse on the right Generalized rod and cone system dysfunction. PERG excluded due to variable fixation Generalized rod and cone system dysfunction BE PERG not performed

P5/M

1.22 0.9 (10)

+1.75/ 3.75 9 180° +2.25/ 4 9 180°

P6/F

0.4 0.5 (5)

+3.5/ 1.5 9 10° +4/ 4/2.0 9 160°

P7/M

0.6 NPL (2)

Myopic astigmatism

Diffuse retinal atrophy, BE macular RPE pigmentary changes, pale optic discs Lacunae of chorioretinal atrophy, pale discs, attenuated vessels

RE lacunae of chorioretinal atrophy with incomplete peripheral retinal vascularization LE retinal detachment

Generalized loss of rod function BE with asymmetrical cone Onpathway involvement, RE > LE PERG evidence of severe macular dysfunction BE Generalized rod and cone system dysfunction BE. PERG evidence of macular dysfunction BE Mild generalized rod and cone system dysfunction BE PERG evidence of macular dysfunction BE Reported as abnormal (no detailed description is available)

c.699-2A>G

Exon

Protein change

p.Arg234Cys

6/7

Acceptor splice site

c.204dup

2

p.Asp69X

c.1039_1040 delCT

9

p.Leu347Glufs*8

4/5

Donor splice site

c.387 + 1G>A

P = patient, F = female, M = male, BCVA = best-corrected visual acuity in LogMAR, RE = right eye, LE = left eye, BE = both eyes, RPE = retinal pigment epithelium, PERG = pattern ERG, NPL = no perception of light. P1 and P2 are sisters, originally described as CDMMR05 in Ostergaard et al. (2012), P3 as CDMMR04, P4 as MLCRD10 and P6 as MLCRD03. P5 and P7 originally described as family II and family IV in Jones et al. (2014).

confirmed KIF11 mutations and represents the largest series to date to undergo detailed structural and functional retinal assessments. It will henceforth contribute to the diagnosis and management of patients with MCLID.

Methods The study was approved by the local ethics committee and adhered to the

principles of the Declaration of Helsinki. All patients have been reported previously (Ostergaard et al. 2012; Jones et al. 2014), but without detailed description of their ocular phenotype. In all patients, clinical assessment included best-corrected visual acuity (BCVA), anterior segment and dilated fundus examination. Fundus photography (TRC-50IA; Topcon, Tokyo, Japan) was done in patients 1, 3, 4 and

6. Three patients (cases 4, 5 and 6) had fundus autofluorescence (FAF) using confocal scanning laser ophthalmoscopy (Spectralis HRA Heidelberg Engineering, Heidelberg, Germany), and two (5 and 6) had FAF using a fundus camera (TRC-50IA; Topcon, Tokyo, Japan). Spectral Domain (SD) OCT (Spectralis HRA-OCT, Heidelberg Engineering, Heidelberg, Germany) was performed in patients 2, 4, 5 and 6.

93


Full-field and pattern electroretinography (ERG, PERG) were performed without sedation. Recording protocols incorporated the ISCEV standard (Marmor et al. 2009; Bach et al. 2013) in cases 1 and 4, with additional On/Off ERGs recorded to an orange stimulus (560 cd/m2, duration 200 ms) with a green background (150 cd/m2) and Scone ERGs to a blue stimulus (445 nm, 80 cd/m2, duration 5 ms) with the orange as background. Patients 5 and 6 were tested using peri-orbital surface electrodes with ISCEV standard stimuli. Two of the youngest patients (2 and 3) underwent testing using periorbital skin electrodes according to a shortened paediatric protocol (Holder and Robson 2006). In the five patients that underwent PERG testing, both a standard (12 9 15°) and large checkerboard field (24 9 30°) were used and responses recorded with corneal (cases 1 and 4) or peri-orbital skin (cases 2, 5 and 6) electrodes (Lenassi et al. 2012). Patient 7 had electrodiagnostic testing performed in a local hospital. The coding sequence of KIF11 was determined by Sanger sequencing as described in detail elsewhere (Ostergaard et al. 2012).

pigmentary changes in patient 1 (Fig. 1A) and more pronounced mottling in patients 4 (Fig. 1C) and 5. Three patients had disc pallor – patients 3, 5 and 6 (Fig. 1D). Patient 7 had a retinal fold in the right eye and a left retinal detachment. Fundus abnormalities were stable over followup periods of 2 (patient 5), 6 (patient 1) and 9 (patient 4) years. Patient 4 had hypoautofluorescence at the macula with adjacent area of hyperautofluorescence most likely due to a window effect. The lesions appear stable on the follow-up images 3 years

later (Fig. 2A). In patient 5, the posterior pole showed diffuse hypoautofluorescence speckled by hyperautofluorescent spots. There was patchy hypoautofluorescence peripapillary and around the macula. The macula was hypoautofluorescent (Fig. 2B). In patient 6, the macula showed normal autofluorescence and was surrounded by a ring-like area of increased autofluorescence extending over temporal and superior–temporal retinal areas (Fig. 2C). The inner boundary of the parafoveal hyperautofluorescent ring corresponded with the

(A)

Results The clinical details of the seven patients appear in Table 1. All were microcephalic with learning difficulties. Cases 4 and 6 had congenital lymphedema of the lower limbs. Best-corrected visual acuity (LogMAR) ranged from 0.12 to 3.0. Patient 7 was blind in his left eye due to retinal detachment. Best-corrected visual acuity improved in patient 1 from 0.4 bilaterally when aged 4 years to 0.12 right and 0.2 left by the age of 10 years. It is difficult to know the significance of this as the testing methods differed at different ages. Most patients were hypermetropic with astigmatism, except for patient 2 who showed only hypermetropia. Myopic astigmatism was documented in patient 7, but an accurate assessment of refraction was not possible. Areas of chorioretinal atrophy outside the arcades associated with pigment clumping were present in all patients (Fig. 1) except patient 5. Patient 5 had diffuse chorioretinal atrophy that included the posterior pole. The maculae showed subtle

94

(B)

(C)

(D) Fig. 1. Fundus photographs of the right and left eye demonstrating the typical areas of chorioretinal atrophy with pigment clumps, macular pigmentary changes and optic disc pallor in patients with KIF11 mutations. (A) patient 1 (B) patient 3 (C) patient 4 (D) patient 6.


2, 4 and 5 (Fig. 3A,B). In patient 6, there was parafoveal disruption of the inner segment ellipsoid and outer retinal bands but with central sparing (Fig. 3C). Electroretinography showed mild– moderate generalized rod and cone photoreceptor involvement in all patients, except case 7 (Table 1; Fig. 4). The ERG of patient 7 was reported as abnormal, but no detailed description was available. There was additional inner retinal dysfunction in patients 1, 2 and 4 with evidence of cone On-pathway involvement (Fig. 4A,B). Pattern ERGs were subnormal (case 1; Fig. 3), undetectable (cases 4-6) or excluded due to variable fixation during testing (case 2).

Discussion (A)

(B)

(C)

Fig. 2. Fundus autofluorescent imaging for the right eye (right) and the left eye (left) in (A) patient 4 shows hypoautofluorescence of the atrophic macula with adjacent hyperfluorescence from a window effect. Follow-up images 3 years later are shown in the lower panel – the lesions appear stable. The difference in the intensity of the hyperautofluorescence is due to changes in the gain compared to the upper panel. (B) patient 5 has diffuse retinal lesions showing hypoautofluorescence with hyperautofluorescent spots and patchy hypoautofluorescence from the atrophic regions around the papilla and in the macula region. Hyperautofluorescence is present at the junction with the normal retina. (C) patient 6 has normal autofluorescence of the macula, surrounded by a ring-like area of hyperautofluorescence. The lacunae of chorioretinal atrophy show hypoautofluorescence.

lateral extent of preserved retina evident in the OCT (Fig. 3C). The lacunae of atrophy were hypoautofluorescent (Fig. 2A,B) although the decreased

signal does not exactly overlap the areas of RPE atrophy. Optical coherence tomography showed severe macular atrophy in cases

This report details the ocular features specifically associated with KIF11 mutations and MCLID. Prior to the identification of KIF11, a variety of ocular findings had been described in association with MCLID, but it was unclear whether this represented variable expression of a single genetic entity or a heterogeneous group of patients with different phenotypes. The data contained in the present report, arising from a molecularly confirmed cohort, clarify some of these issues. Patients were generally hypermetropic with astigmatism, but one patient (patient 7) had myopic astigmatism as previously reported (Sadler & Robinson 1993). Visual acuity showed marked variability even within families (e.g. patients 1 and 2 – sisters carrying identical mutation). Although both eyes are invariably affected, interocular asymmetry is possible (e.g. patient 7). Most patients showed chorioretinal dysplasia, in keeping with previous reports (Tenconi et al. 1981; Warburg & Heuer 1994; Atchaneeyasakul et al. 1998; Gupta et al. 2009), although this finding could be confounded by ascertainment bias. The fundus appearance is characterized by lacunae of chorioretinal atrophy with vessel attenuation and pigment clumping, generally located outside the arcades, sparing the macula. The chorioretinal atrophic lacunae were evident at presentation and are probably congenital. One patient in the present series (patient 4) has shown no significant change in these lesions over a 9-year follow-up, indicating that the lesions are most

95


(A)

(C)

(D)

(B)

Fig. 3. Optical coherence tomography (OCT) imaging for the right eye (upper panels) and left eye (lower panels) in (A) patient 2, (B) patient 4, (C) patient 5 and (D) patient 6. The images show atrophic changes at the macula in patients 2, 4 and 5. Patient 6 shows disruption of the outer retinal bands outside the macula.

likely non-progressive (Manning et al. 1990; Warburg & Heuer 1994). The peripheral retina in most patients appeared dystrophic, with diffuse RPE disturbance. Three patients (43%) had pigmentary changes at the maculae. The atrophic changes of the maculae were clearly demonstrated by the FAF and OCT imaging. The follow-up FAF images after 3 years showed similar changes. However, longer follow-up with autofluorescence and OCT imaging will be important to confirm that there is no progression. The electrophysiological data usually showed generalized dysfunction of both rod and cone systems, in keeping with the peripheral retinal appearance described above, and predominantly at the level of the photoreceptors; if the abnormal function was simply confined to the areas of atrophy, amplitude reduction may have occurred, but without associated peak-time shift. In this series, the ERGs were of borderline timing in case 1 but all others showed some evidence of significant delay in at least one ERG parameter, suggesting

96

generalized retinal dysfunction. There are few reports of retinal electrophysiology in association with MCLID in the literature (Manning et al. 1990; Feingold & Bartoshesky 1992; Atchaneeyasakul et al. 1998; Hazan et al. 2012), and most previously published data were acquired prior to the identification of KIF11 as the causative gene, with the largest ERG series acknowledging the likelihood of heterogeneity (Atchaneeyasakul et al. 1998). As in the present series, ERG data from one family with confirmed KIF11 mutation (Hazan et al. 2012) and another with dominant inheritance but without molecular data (Simonell et al. 2002) showed subnormal and delayed rod and cone ERGs. The present report represents the largest series to date of ERGs in patients with confirmed KIF11 mutation. The On–Off ERG data are novel and suggest possible additional inner retinal dysfunction in some patients. There has been no previous report of PERG findings; the PERG data are in keeping with macular dysfunction in all patients tested.

‘Microcephaly and chorioretinal dysplasia’ and ‘microcephaly and retinal folds’ have previously been suggested to be allelic conditions (Angle et al. 1994; Fryns et al. 1995). One subject in the present study has vascular abnormalities in addition to the typical chorioretinal atrophy in one eye. A previous report described two siblings, one with the typical chorioretinal atrophy but the other with retinal folds (Trzupek et al. 2007). Two further siblings with MCLID have been reported where one had the typical punched out chorioretinal lesions, but the other unilateral persistent hyperplastic primary vitreous (PHPV), cataract and microphthalmia (Casteels et al. 2001). The data therefore indicate clinical overlap between MCLID and microcephaly with retinal folds. In a recent report, KIF11 mutations have been found in patients with clinical diagnosis of familial exudative vitreoretinopathy (FEVR). Three of the patients had retinal folds (Robitaille et al. 2014). However, most patients within our cohort with ‘microcephaly


(A)

(B)

(C)

Fig. 4. Full-field electroretinography (ERGs) and pattern ERGs (PERG) in (A) patient 1, (B) patient 4 (right eye – upper panels, left eye – lower panels) and (C) normal control. Dark-adapted responses are shown for flash strengths of 0.01 and 11.0 cd s/m2 (DA 0.01; DA 11.0); light-adapted ERGs are shown for flash strength 3.0 cd s/m2 (LA 3.0; 30 Hz and 2 Hz). Photopic On/Off ERGs in both patients show evidence of possible Onpathway dysfunction (asymmetrical in case 4). S-cone ERGs in case 4 are severely reduced. For clarity, broken lines replace blink artefacts in the DA 11.0 ERGs.

with retinal folds’ are negative for KIF11 mutations, suggesting that another gene is more often responsible for that condition. The retinal anomalies in patients with MCLID suggest that the underlying KIF11 mutation may affect both retinal and choroidal vascular development; vascular events in utero could cause focal areas of ischaemia and subsequent chorioretinal atrophy. Moreover, patients with KIF11 mutations have been shown to have vascular abnormalities and nonperfused areas on fluorescein angiography (Robitaille et al. 2014). Further studies are necessary to investigate the exact pathogenesis.

To conclude, the present series adds significantly to our knowledge of the phenotypic characteristics associated with KIF11 mutation, enabling more accurate diagnosis and management of patients with this rare disorder.

References Angle B, Holgado S, Burton BK, Miller MT, Shapiro MJ & Opitz JM (1994): Microcephaly, lymphedema, and chorioretinal dysplasia: report of two additional cases. Am J Med Genet 53: 99–101. Atchaneeyasakul LO, Linck L & Weleber RG (1998): Microcephaly with chorioretinal degeneration. Ophthalmic Genet 19: 39–48.

Bach M, Brigell MG, Hawlina M, Holder GE, Johnson MA, McCulloch DL, Meigen T & Viswanathan S (2013): ISCEV standard for clinical pattern electroretinography (PERG): 2012 update. Doc Ophthalmol 126: 1–7. Blangy A, Lane HA, d’Herin P, Harper M, Kress M & Nigg EA (1995): Phosphorylation by p34cdc2 regulates spindle association of human Eg5, a kinesin-related motor essential for bipolar spindle formation in vivo. Cell 83: 1159–1169. Casteels I, Devriendt K, Van Cleynenbreugel H, Demaerel P, De Tavernier F & Fryns JP (2001): Autosomal dominant microcephaly– lymphoedema-chorioretinal dysplasia syndrome. Br J Ophthalmol 85: 499–500. Feingold M & Bartoshesky L (1992): Microcephaly, lymphedema, and chorioretinal

97


dysplasia: a distinct syndrome? Am J Med Genet 43: 1030–1031. Fryns JP, Smeets E & Van den Berghe H (1995): On the nosology of the “primary true microcephaly, chorioretinal dysplasia, lymphoedema” association. Clin Genet 48: 131– 133. Gupta A, Vasudevan P, Biswas S, Smith JC, Moore AT, Lloyd C & Dutton G (2009): Microcephaly with chorioretinal dysplasia: two case reports and a review of the literature. Ophthalmic Genet 30: 157–160. Hazan F, Ostergaard P, Ozturk T, Kantekin E, Atlihan F, Jeffery S & Ozkinay F (2012): A novel KIF11 mutation in a Turkish patient with microcephaly, lymphedema, and chorioretinal dysplasia from a consanguineous family. Am J Med Genet A 158A: 1686–1689. Holder GE, Robson AG (2006): Paediatric electrophysiology: a practical approach. In: Lorenz B, Moore AT (eds.). Paediatric ophthalmology, neuro-ophthalmology, genetics Heidelberg: Springer. Jarmas AL, Weaver DD, Ellis FD & Davis A (1981): Microcephaly, microphthalmia, falciform retinal folds, and blindness. A new syndrome. Am J Dis Child 135: 930–933. Jones GE, Ostergaard P, Moore AT et al. (2014): Microcephaly with or without chorioretinopathy, lymphoedema, or mental retardation (MCLMR): review of phenotype associated with KIF11 mutations. Eur J Hum Genet 22: 881–887. Lenassi E, Robson AG, Hawlina M & Holder GE (2012): The value of two-field pattern electroretinogram in routine clinical electrophysiologic practice. Retina 32: 588–599.

98

Manning FJ, Bruce AM & Berson EL (1990): Electroretinograms in microcephaly with chorioretinal degeneration. Am J Ophthalmol 109: 457–463. Marmor MF, Fulton AB, Holder GE, Miyake Y, Bach M (2009): International Society for Clinical Electrophysiology of Vision. ISCEV standard for full field electroretinography (2008 update). Doc Ophthalmol 118: 69–77. Ostergaard P, Simpson MA, Mendola A et al. (2012): Mutations in KIF11 cause autosomal-dominant microcephaly variably associated with congenital lymphedema and chorioretinopathy. Am J Hum Genet 90: 356–362. Robitaille JM, Gillett RM, LeBlanc MA et al. (2014): Phenotypic overlap between familial exudative vitreoretinopathy and microcephaly, lymphedema, and chorioretinal dysplasia caused by KIF11 mutations. JAMA Ophthalmol 132: 1393–1399. Sadler LS & Robinson LK (1993): Chorioretinal dysplasia-microcephaly-mental retardation syndrome: report of an American family. Am J Med Genet 47: 65–68. Simonell F, Testa F, Nesti A, de Crecchio G, Bifani M, Cavaliere ML, Rinaldi E & Rinaldi MM (2002): An Italian family affected by autosomal dominant microcephaly with chorioretinal degeneration. J Pediatr Ophthalmol Strabismus 39: 288– 292. Tenconi R, Clementi M, Moschini GB, Casara G & Baccichetti C (1981): Chorio-retinal dysplasia, microcephaly and mental retardation. An autosomal dominant syndrome. Clin Genet 20: 347–351. Trzupek KM, Falk RE, Demer JL & Weleber RG (2007): Microcephaly with

chorioretinopathy in a brother-sister pair: evidence for germ line mosaicism and further delineation of the ocular phenotype. Am J Med Genet A 143A: 1218–1222. Warburg M & Heuer HE (1994): Chorioretinal dysplasia-microcephaly-mental retardation syndrome. Am J Med Genet 52: 117. Young ID, Fielder AR & Simpson K (1987): Microcephaly, microphthalmos, and retinal folds: report of a family. J Med Genet 24: 172–174.

Received on November 10th, 2014. Accepted on April 6th, 2015. Correspondence: Anthony T. Moore Professorial Unit Moorfields Eye Hospital 162 City Road EC1V 2PD London UK Tel: 0207 566 2260 Fax: +1 415 476 0336 Email: [email protected] The authors would like to thank the families for agreeing to the publication of their clinical details and photographs. We would like to acknowledge Fight for Sight (UK), Foundation Fighting Blindness (USA) and National Institute for Health Research (Moorfields BRC) for funding. We would also like to thank the British Heart Foundation (PG/10/58/28477 for PO).

Microcephaly with or without chorioretinopathy, lymphoedema, or mental retardation (MCLMR): review of phenotype associated with KIF11 mutations.

Autosomal Dominant Microcephaly Associated With Congenital Lymphedema and Chorioretinopathy Due to a Novel Mutation in KIF11.

Mutations in SPATA5 Are Associated with Microcephaly, Intellectual Disability, Seizures, and Hearing Loss.

Phenotypic overlap between familial exudative vitreoretinopathy and microcephaly, lymphedema, and chorioretinal dysplasia caused by KIF11 mutations.

De novo mutations in moderate or severe intellectual disability.

Congenital microcephaly and chorioretinopathy due to de novo heterozygous KIF11 mutations: five novel mutations and review of the literature.

Mutations in HECW2 are associated with intellectual disability and epilepsy.

Symptoms and development of anxiety in children with or without intellectual disability.

A syndrome of congenital microcephaly, intellectual disability and dysmorphism with a homozygous mutation in FRMD4A.

Novel IL1RAPL1 mutations associated with intellectual disability impair synaptogenesis.

DYRK1A haploinsufficiency causes a new recognizable syndrome with microcephaly, intellectual disability, speech impairment, and distinct facies.

Mutations specific to the Rac-GEF domain of TRIO cause intellectual disability and microcephaly.

Mutations in PTRH2 cause novel infantile-onset multisystem disease with intellectual disability, microcephaly, progressive ataxia, and muscle weakness.

Mutations in epilepsy and intellectual disability genes in patients with features of Rett syndrome.

Mediating Community Participation: Practice of Support Workers in Initiating, Facilitating or Disrupting Encounters between People with and without Intellectual Disability.

TAF1 Variants Are Associated with Dysmorphic Features, Intellectual Disability, and Neurological Manifestations.

GRIN2B mutations in West syndrome and intellectual disability with focal epilepsy.

Mutations in the DNA methyltransferase gene DNMT3A cause an overgrowth syndrome with intellectual disability.

Identical by descent L1CAM mutation in two apparently unrelated families with intellectual disability without L1 syndrome.

A homozygous mutation in SLC1A4 in siblings with severe intellectual disability and microcephaly.

A newly recognized syndrome of severe growth deficiency, microcephaly, intellectual disability, and characteristic facial features.

NR2F1 mutations cause optic atrophy with intellectual disability.

Mutations in the histamine N-methyltransferase gene, HNMT, are associated with nonsyndromic autosomal recessive intellectual disability.

Application of array comparative genomic hybridization in 256 patients with developmental delay or intellectual disability.