Begemann, Anais

Joset, Pascal

Kaariainen, Helena

Oneda, Beatrice

Peippo, Maarit M.

Pöyhönen, Minna

Rauch, Anita

Zweier, Markus

Markus Zweier

Maarit M. Peippo

Minna Pöyhönen

Helena Kääriäinen

Anaïs Begemann

Pascal Joset

Beatrice Oneda

Anita Rauch

Crossref

American Journal of Medical Genetics Part A

The HHID syndrome of hypertrichosis, hyperkeratosis, abnormal corpus callosum, intellectual disability, and minor anomalies is caused by mutations in
            <i>ARID1B</i>

Kääriäinen, Helena

Begemann, Anaïs

Repository for Publications and Research Data

The HHID syndrome of hypertrichosis, hyperkeratosis, abnormal corpus callosum, intellectual disability, and minor anomalies is caused by mutations in ARID1B

Helsingin yliopiston digitaalinen arkisto

Received: 21 December 2016 | Accepted: 22 December 2016DOI 10.1002/ajmg.a.38143RESEARCH LETTERThe HHID syndrome of hypertrichosis, hyperkeratosis,abnormal corpus callosum, intellectual disability, and minoranomalies is caused by mutations in ARID1BMarkus Zweier1 | Maarit M. Peippo2 | Minna Pöyhönen3 | Helena Kääriäinen4 |Anaïs Begemann1,5 | Pascal Joset1 | Beatrice Oneda1 | Anita Rauch1,5,6,71 Institute of Medical Genetics, University ofZurich, Schlieren-Zurich, Switzerland2Mehiläinen Clinic, Vantaa, Finland3Department of Clinical Genetics, HelsinkiUniversity Central Hospital and Department ofMedical Genetics, University of Helsinki,Helsinki, Finland4National Institute for Health and Welfare,Helsinki, Finland5Radiz–Rare Disease Initiative Zurich, ClinicalResearch Priority Program for Rare Diseases,University of Zurich, Zurich, Switzerland6 Zurich Center for Integrative HumanPhysiology, University of Zurich, Zurich,Switzerland7Neuroscience Center Zurich, University ofZurich and ETH Zurich, Zurich, SwitzerlandCorrespondenceAnita Rauch, Institute of Medical Genetics,University of Zurich, Wagistrasse 12, 8592Schlieren-Zurich, Switzerland.Email: anita.rauch@medgen.uzh.chK E YWORD Sabnormal corpus callosum, ARID1B, Coffin-Siris syndrome, HHID, hyperkeratosis, hypertrichosis,intellectual disability, minor anomaliesTO THE EDITOR:In 2004, Pöyhönen et al. reported on three unrelated patientswithhypertrichosis, hyperkeratosis, abnormal corpus callosum, intellectualdisability (ID), and minor anomalies including low anterior hairline,thick arched eyebrows, broad nasal tip, columella below alae nasi,short philtrum, thick-everted lower lip, simple posteriorly angulatedears, and broad feet and finger tips (Pöyhönen et al., 2004). Thisobservation was recognized as an OMIM entity (OMIM 609943),hereafter referred to as HHID syndrome. In 2009, Dalal and Mehrotra(2009) reported a further patient with HHID syndrome whoadditionally presented with short stature, short 4th and 5th toes,mild dilatation of the supratentorial ventricular system andnephrolithiasis. No further individual with suspected HHID has beenpublished and the cause of their condition remained elusive. We nowused whole exome sequencing (WES) in the three patients publishedby Pöyhönen et al. (2004) and discuss the updated phenotype in thelight of today’s clinical knowledge and our genetic findings.The detailed initial clinical description of patient 1 (P1, at age of 16years), patient 2 (P2, at age of 17 years), and patient 3 (P3, at age of 10years), all born to non-consanguineous parents from different parts ofFinland, is provided in the original article by Pöyhönen et al. (2004).Clinical reassessmentof the threepatients after about10years revealedthe previously described phenotype, except for hypertrichosis, whichnow resembled normal variation. Additionally, behavior anomalies suchas severe obsessive-compulsive and autistic behavior and a hoarse orhigh pitched voice were noted (Table 1, Figure 1).This is an open access article under the terms of the Creative Commons Attribution-NonCommercial-NoDerivs License, which permits use and distribution in anymedium, provided the original work is properly cited, the use is non-commercial and no modifications or adaptations are made.© 2017 The Authors. American Journal of Medical Genetics Part A Published by Wiley Periodicals, Inc.1440 | wileyonlinelibrary.com/journal/ajmga Am J Med Genet. 2017;173A:1440–1443.Results of conventional karyotyping, subtelomeric FISH studiesand targeted testing of CREBBP were normal. We then performedhigh resolution chromosomal microarray testing which did not revealany apparent pathologic variant followed by WES in P1 and trio-WES in P2 and P3 and their healthy parents. The study wasapproved by the ethical committee of the canton of Zurich. Filteringfor rare, non-synonymous exonic, and splice site variants in 821known and 424 candidate ID genes (based on the SysID database,[Kochinke et al., 2016]), considering both dominant and recessivemodes of inheritance, revealed pathogenic de novo loss of functionmutations in ARID1B in P2 and P3. In P2, we identified aheterozygous deletion of 4 bp (NM_020732.3:c.5570_5573del) inthe last coding exon of ARID1B, which causes a frameshift resultingin a premature truncation after 16 amino acids and thereafter aTABLE 1 Updated clinical features of HHID patientsPatients P1 P2 P3Genetic defect Unknown ARID1B: c.5570_5573del(p.Lys1857Serfs*17)ARID1B: c.4110G>A(p.His1339Ilefs*77)Age atinvestigation25 y 26 y 19 yGrowthparametersHeight 156.3 cm (−1.6 SD) 155 cm (−1.8 SD) 154.5 cm (−1.8 SD)OFC 55 cm (0 SD) 56.5 cm (+1 SD) 54.5 cm (−0.5 SD)BMI 19.3 32 25.1Menarche 9 y 13 y 15 yHealthMalformations Thick and short corpus callosum VSD, PDA, mild CoA. Cong. hip dislocation,midline supraumbilical hernia, cong. ptosis ofright eye, no cerebral MRIThick and short corpus callosumVision Strabism, myopia right, hyperopia left Strabism, myopia MyopiaGeneral Recurrent ear infections—tubeinsertion & adenotomy (5 y) enuresisup to 10 yRecurrent ear infections—tube insertion &adenotomy (7 y) hemicraniaSevere atopic eczemaEctodermal signsHypertrichosis Vanished Vanished VanishedHyperkeratoticskin plaquesNeck, shoulders, axillary area, betweenthe breasts, and on the lowerabdominal and dorsal areasMiddle of the back Lower and upper limbsNails Mild hypoplasia Mild hypoplasia Mild hypoplasiaBehaviour &developmentWalking 1 y 8mo 2 y 4mo 1 y 6moSpeechdevelopment(sentences)2 y 4 y 5 yAcademicachievementsReads, writes, counts Reads, writes, counts Reads, writes, countsID Mild Mild-moderate MildVoice & speechbehaviourVoice hoarse, increasing inertia tospeakVoice hoarse, feeble; speech slurred, finallytotal refusal to speakVoice high pitched; slurredspeech, rapid change of pitch,diminishing use of speechSleepingproblemsreverse sleeping rhythm No NoBehaviour/personalityWithdrawn, stubborn, irritated,passive, temper tantrums, detestspresence of othersWithdrawn, obstinate, passive, obsessive-compulsive, detests presence of othersWithdrawn, autistic, obsessivecompulsive, detests presenceof othersCognitiveregressionNo (severe visuospatial and motorproblems)No Noy, years; mo, month; OFC, occipito-frontal circumference; BMI, body mass index; SD, standard deviation score; MRI, magnetic resonance imaging; VSD,ventricular septal defect; PDA, patent ductus arteriosus; CoA., coaxial; Cong., congenital; ID, intellectual disability.ZWEIER ET AL. | 1441significantly truncated protein (p.Lys1857Serfs*17). This mutationhas not been reported before and de novo occurrence wasconfirmed by Sanger sequencing in the patient and her parents.WES in P3 and her parents revealed a heterozygous de novomutation of the last coding basepair of exon 17 (NM_020732.3:c.4110G>A), which was predicted to be synonymous, but located inthe conserved consensus splice donor site. This mutation had beenreported previously in a patient with nonspecific ID and results inskipping of exon 17 in RNA from patient lymphocytes (Hoyer et al.,2012). Therefore, it was predicted to cause a frameshift resulting in apremature translational termination (p.His1339Ilefs*77); and thus,possibly in nonsense-mediated mRNA-decay. In P1, no obviouspathogenic or likely pathogenic loss of function mutation in a knownID gene could be detected, although the whole coding region ofARID1B was covered at least 20-fold and MLPA analysis showednormal dosage for all exons. Of note, additional mutation screeningof all variants in related ID genes (ARID1B, SMARCA4, SMARCB1,SMARCE1, SMARCA2, TBC1D24, SOX11, PHF6, TBC1D24, ADNP, andKMT2A) revealed no obvious pathogenic variant, either. However,interpretation of missense variants in other genes and analysis ofnovel candidate genes were hampered by the fact that the fatherwas not available and a trio approach therefore not feasible.Our findings establish mutations in ARID1B as the underlyinggenetic defect in the HHID syndrome in two of three patients.The underlying genetic defect in P1 remains currently elusive,however, an undetected non-coding mutation of ARID1B cannot beexcluded.Haploinsufficiency of ARID1B was recently implicated in both,nonsyndromic ID and Coffin-Siris Syndrome (CSS, OMIM #135900)(Hoyer et al., 2012; Santen et al., 2012; Tsurusaki et al., 2012). There isaccumulating evidence that ARID1B is one of the most commonlymutated genes in ID and is associated with a broad phenotypic range(Deciphering Developmental Disorders, 2015; Hoyer et al., 2012;Santen & Clayton-Smith, 2014). The core phenotype of ARID1Bmutated patients, present in almost all patients with a prior CSSdiagnosis, comprises ID (100%), speech delay (100%), “coarse facies”(95%), and hypertrichosis (95%). Common further anomalies weresmall 5th finger or toe nails (81%), short fifth finger (73%), feedingdifficulties (65%), agenesis of the corpus callosum (35%), seizures(23%), myopia (20%), and growth delay (19% height <−2.5 SDS, 71%height <0 SDS) (Santen & Clayton-Smith, 2014). Retrospectively, theHHID patients’ phenotypes fit well into the published ARID1B-associated clinical spectrum including the key features of ID,hypertrichosis, abnormal corpus callosum, and coarse face. However,our patients show only mildly diminished nail size and demonstratethat the key feature of hypertrichosis vanishes to levels of normalvariation during adolescence. Moreover, the most distinctive featureshared by all patients with suspected HHID (Dalal & Mehrotra, 2009;Pöyhönen et al., 2004) is the ectodermal sign of hyperkeratoticplaques which has not yet been reported in any patient with CSS orARID1B-associated nonspecific ID. This might therefore constituteeither an underreported or an infrequent but distinct novel feature ofARID1B-associated phenotypes. However, reevaluation of patientswith ARID1B mutations is needed to assess the true incidence ofFIGURE 1 Phenotypes of patients with suspected HHID syndrome at clinical reinvestigation after about 10 years. Facial gestalt, hand andfoot, and a location with hyperkeratotic plaques is shown for P1 at the age of 25 years (A-E), for P2 at the age of 26 years (F-J), and for P3 atthe age of 19 years (K-N). Of note, the picture with hyperkeratotic plaques for P3 (O) was taken at the age of 16 years1442 | ZWEIER ET AL.hyperkeratotic plaques, which may become only obvious withincreasing age.REFERENCESDalal, A., & Mehrotra, R. N. (2009). Hypertrichosis, hyperkeratosis andmental retardation syndrome: Further delineation of phenotype.Clinical Dysmorphology, 18, 83–84.Deciphering Developmental Disorders S. (2015). Large-scale discovery ofnovel genetic causes of developmental disorders.Nature, 519, 223–228.Hoyer, J., Ekici, A. B., Endele, S., Popp, B., Zweier, C., Wiesener, A., . . . Reis,A. (2012). Haploinsufficiency of ARID1B, a member of the SWI/SNF-achromatin-remodeling complex, is a frequent cause of intellectualdisability. The American Journal of Human Genetics, 90, 565–572.Kochinke, K., Zweier, C., Nijhof, B., Fenckova, M., Cizek, P., Honti, F., . . .Schenck, A. (2016). Systematic phenomics analysis deconvolutes genesmutated in intellectual disability into biologically coherentmodules. TheAmerican Journal of Human Genetics, 98, 149–164.Pöyhönen, M. H., Peippo, M. M., Valanne, L. K., Kuokkanen, K. E., Koskela,S. M., Bartsch, O., . . . Kääriäinen, H. A. (2004). Hypertrichosis,hyperkeratosis, abnormal corpus callosum, mental retardation anddysmorphic features in three unrelated females. Clinical Dysmorphology,13, 85–90.Santen, G. W., & Clayton-Smith, J. (2014). The ARID1B phenotype: Whatwe have learned so far. The American Journal of Human Genetics Part C:Seminars in Medical Genetics, 166C, 276–289.Santen,G.W., Aten, E., Sun, Y., Almomani, R., Gilissen, C., Nielsen,M., . . .Kriek,M. (2012). Mutations in SWI/SNF chromatin remodeling complex geneARID1B cause Coffin-Siris syndrome. Nature Genettics, 44, 379–380.Tsurusaki, Y., Okamoto, N., Ohashi, H., Kosho, T., Imai, Y., Hibi-Ko, Y., . . .Matsumoto,N. (2012).Mutations affecting components of the SWI/SNFcomplex cause Coffin-Siris syndrome. Nature Genetics, 44, 376–378.How to cite this article: Zweier M, Peippo MM, PöyhönenM, et al. The HHID syndrome of hypertrichosis,hyperkeratosis, abnormal corpus callosum, intellectualdisability, and minor anomalies is caused by mutations inARID1B. Am J Med Genet Part A. 2017;173A:1440–1443.https://doi.org/10.1002/ajmg.a.38143ZWEIER ET AL. | 1443

Peippo, Maarit M

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The HHID syndrome of hypertrichosis, hyperkeratosis, abnormal corpus callosum, intellectual disability, and minor anomalies is caused by mutations in ARID1B

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