De Novo Variants in the ATPase Module of MORC2 Cause a Neurodevelopmental Disorder with Growth Retardation and Variable Craniofacial Dysmorphism
2020; Elsevier BV; Volume: 107; Issue: 2 Linguagem: Inglês
10.1016/j.ajhg.2020.06.013
ISSN1537-6605
AutoresMaría J. Guillen Sacoto, Iva A. Tchasovnikarova, Erin Torti, Cara Forster, E. Hallie Andrew, Irina Anselm, Kristin Barañano, Lauren C. Briere, Julie S. Cohen, William J. Craigen, Cheryl Cytrynbaum, Nina Ekhilevitch, Matthew J. Elrick, Ali Fatemi, Jamie L. Fraser, Renata C. Gallagher, Andrea Guerin, Devon Haynes, Frances A. High, Cara Inglese, Courtney Kiss, Mary Kay Koenig, Joel B. Krier, Kristin Lindstrom, Michael Marble, Hannah Meddaugh, Ellen Moran, Chantal F. Morel, Weiyi Mu, Eric Muller, Jessica Nance, Marvin R. Natowicz, Adam L. Numis, Bridget Ostrem, John Pappas, Carl E. Stafstrom, Haley Streff, David A. Sweetser, Marta Szybowska, Melissa Walker, Wei Wang, Karin Weiss, Rosanna Weksberg, Patricia G. Wheeler, Grace Yoon, Robert E. Kingston, Jane Juusola,
Tópico(s)RNA modifications and cancer
ResumoMORC2 encodes an ATPase that plays a role in chromatin remodeling, DNA repair, and transcriptional regulation. Heterozygous variants in MORC2 have been reported in individuals with autosomal-dominant Charcot-Marie-Tooth disease type 2Z and spinal muscular atrophy, and the onset of symptoms ranges from infancy to the second decade of life. Here, we present a cohort of 20 individuals referred for exome sequencing who harbor pathogenic variants in the ATPase module of MORC2. Individuals presented with a similar phenotype consisting of developmental delay, intellectual disability, growth retardation, microcephaly, and variable craniofacial dysmorphism. Weakness, hyporeflexia, and electrophysiologic abnormalities suggestive of neuropathy were frequently observed but were not the predominant feature. Five of 18 individuals for whom brain imaging was available had lesions reminiscent of those observed in Leigh syndrome, and five of six individuals who had dilated eye exams had retinal pigmentary abnormalities. Functional assays revealed that these MORC2 variants result in hyperactivation of epigenetic silencing by the HUSH complex, supporting their pathogenicity. The described set of morphological, growth, developmental, and neurological findings and medical concerns expands the spectrum of genetic disorders resulting from pathogenic variants in MORC2. MORC2 encodes an ATPase that plays a role in chromatin remodeling, DNA repair, and transcriptional regulation. Heterozygous variants in MORC2 have been reported in individuals with autosomal-dominant Charcot-Marie-Tooth disease type 2Z and spinal muscular atrophy, and the onset of symptoms ranges from infancy to the second decade of life. Here, we present a cohort of 20 individuals referred for exome sequencing who harbor pathogenic variants in the ATPase module of MORC2. Individuals presented with a similar phenotype consisting of developmental delay, intellectual disability, growth retardation, microcephaly, and variable craniofacial dysmorphism. Weakness, hyporeflexia, and electrophysiologic abnormalities suggestive of neuropathy were frequently observed but were not the predominant feature. Five of 18 individuals for whom brain imaging was available had lesions reminiscent of those observed in Leigh syndrome, and five of six individuals who had dilated eye exams had retinal pigmentary abnormalities. Functional assays revealed that these MORC2 variants result in hyperactivation of epigenetic silencing by the HUSH complex, supporting their pathogenicity. The described set of morphological, growth, developmental, and neurological findings and medical concerns expands the spectrum of genetic disorders resulting from pathogenic variants in MORC2. Microrchidia CW-type zinc finger protein 2 (MORC2, MIM: 616661) is a member of a family of ATPases fundamental for epigenetic silencing through chromatin modification.1Moissiard G. Cokus S.J. Cary J. Feng S. Billi A.C. Stroud H. Husmann D. Zhan Y. Lajoie B.R. McCord R.P. et al.MORC family ATPases required for heterochromatin condensation and gene silencing.Science. 2012; 336: 1448-1451Crossref PubMed Scopus (220) Google Scholar, 2Tchasovnikarova I.A. Timms R.T. Douse C.H. Roberts R.C. Dougan G. Kingston R.E. Modis Y. Lehner P.J. Hyperactivation of HUSH complex function by Charcot-Marie-Tooth disease mutation in MORC2.Nat. Genet. 2017; 49: 1035-1044Crossref PubMed Scopus (68) Google Scholar, 3Li D.Q. Nair S.S. Ohshiro K. Kumar A. Nair V.S. Pakala S.B. Reddy S.D. Gajula R.P. Eswaran J. Aravind L. Kumar R. MORC2 signaling integrates phosphorylation-dependent, ATPase-coupled chromatin remodeling during the DNA damage response.Cell Rep. 2012; 2: 1657-1669Abstract Full Text Full Text PDF PubMed Scopus (93) Google Scholar It has most commonly been associated with autosomal-dominant Charcot-Marie-Tooth (CMT) disease type 2Z (MIM: 616688), a form of axonal neuropathy with progressive weakness, muscle cramps, and sensory impairment presenting in childhood or early adulthood.4Sevilla T. Lupo V. Martínez-Rubio D. Sancho P. Sivera R. Chumillas M.J. García-Romero M. Pascual-Pascual S.I. Muelas N. Dopazo J. et al.Mutations in the MORC2 gene cause axonal Charcot-Marie-Tooth disease.Brain. 2016; 139: 62-72Crossref PubMed Scopus (58) Google Scholar, 5Ando M. Okamoto Y. Yoshimura A. Yuan J.H. Hiramatsu Y. Higuchi Y. Hashiguchi A. Mitsui J. Ishiura H. Fukumura S. et al.Clinical and mutational spectrum of Charcot-Marie-Tooth disease type 2Z caused by MORC2 variants in Japan.Eur. J. Neurol. 2017; 24: 1274-1282Crossref PubMed Scopus (24) Google Scholar, 6Laššuthová P. Šafka Brožková D. Krůtová M. Mazanec R. Züchner S. Gonzalez M.A. Seeman P. Severe axonal Charcot-Marie-Tooth disease with proximal weakness caused by de novo mutation in the MORC2 gene.Brain. 2016; 139: e26Crossref PubMed Scopus (22) Google Scholar, 7Semplicini C. Ollagnon-Roman E. Leonard-Louis S. Piguet-Lacroix G. Silvestre M. Latour P. Stojkovic T. High intra-familiar clinical variability in MORC2 mutated CMT2 patients.Brain. 2017; 140: e21Crossref PubMed Scopus (10) Google Scholar However, some reported individuals presented with hypotonia, generalized muscle weakness, and delayed milestones,4Sevilla T. Lupo V. Martínez-Rubio D. Sancho P. Sivera R. Chumillas M.J. García-Romero M. Pascual-Pascual S.I. Muelas N. Dopazo J. et al.Mutations in the MORC2 gene cause axonal Charcot-Marie-Tooth disease.Brain. 2016; 139: 62-72Crossref PubMed Scopus (58) Google Scholar or occasionally with spinal muscular atrophy, intellectual disability, hearing loss, pyramidal signs, microcephaly, and brain atrophy, in infancy.4Sevilla T. Lupo V. Martínez-Rubio D. Sancho P. Sivera R. Chumillas M.J. García-Romero M. Pascual-Pascual S.I. Muelas N. Dopazo J. et al.Mutations in the MORC2 gene cause axonal Charcot-Marie-Tooth disease.Brain. 2016; 139: 62-72Crossref PubMed Scopus (58) Google Scholar,5Ando M. Okamoto Y. Yoshimura A. Yuan J.H. Hiramatsu Y. Higuchi Y. Hashiguchi A. Mitsui J. Ishiura H. Fukumura S. et al.Clinical and mutational spectrum of Charcot-Marie-Tooth disease type 2Z caused by MORC2 variants in Japan.Eur. J. Neurol. 2017; 24: 1274-1282Crossref PubMed Scopus (24) Google Scholar,8Albulym O.M. Kennerson M.L. Harms M.B. Drew A.P. Siddell A.H. Auer-Grumbach M. Pestronk A. Connolly A. Baloh R.H. Zuchner S. et al.MORC2 mutations cause axonal Charcot-Marie-Tooth disease with pyramidal signs.Ann. Neurol. 2016; 79: 419-427Crossref PubMed Scopus (34) Google Scholar, 9Zanni G. Nardella M. Barresi S. Bellacchio E. Niceta M. Ciolfi A. Pro S. D’Arrigo S. Tartaglia M. Bertini E. De novo p.T362R mutation in MORC2 causes early onset cerebellar ataxia, axonal polyneuropathy and nocturnal hypoventilation.Brain. 2017; 140: e34Crossref PubMed Scopus (13) Google Scholar, 10Schottmann G. Wagner C. Seifert F. Stenzel W. Schuelke M. MORC2 mutation causes severe spinal muscular atrophy-phenotype, cerebellar atrophy, and diaphragmatic paralysis.Brain. 2016; 139: e70Crossref PubMed Scopus (27) Google Scholar The association of MORC2 variants with human disease has only recently been noted, and most of the individuals were ascertained through studies of neuropathies. We used a hypothesis-free approach to assess common characteristics in individuals with de novo variants in MORC2 who were referred for exome sequencing at a clinical laboratory. We identified 15 individuals with de novo variants in MORC2. In addition we included an affected mother-daughter pair harboring a novel variant in MORC2 (subjects 19 and 20) and three individuals heterozygous for recurrent variants for whom parental studies could not be completed (subjects 5, 13, and 16), bringing our total to 20 individuals. Clinical data were obtained from the referring providers or via provider completion of a questionnaire. This study was conducted under GeneDx’s research protocol “Research to Expand the Understanding of Genetic Variants: Clinical and Genetic Correlations,” approved by the Western Institutional Review Board (IRB) (protocol 20171030). All research subjects provided written consent to participate through either GeneDx’s research protocol or as required by their clinical institution. Where applicable, informed written consent was obtained for the use of photographs. For all subjects except subject 9, we used genomic DNA from the proband and parents (when available) to capture the exonic regions and flanking splice junctions of the genome via the SureSelect Human All Exon V4 (50 Mb), the Clinical Research Exome kit (Agilent Technologies), or the IDT xGen Exome Research Panel v1.0. Massively parallel (NextGen) sequencing was done on an Illumina system with 100 bp or greater paired-end reads. Reads were aligned to human genome build GRCh37/UCSC hg19 and analyzed for sequence variants via a custom-developed analysis tool. Additional sequencing technology and the variant interpretation protocol have been previously described.11Retterer K. Juusola J. Cho M.T. Vitazka P. Millan F. Gibellini F. Vertino-Bell A. Smaoui N. Neidich J. Monaghan K.G. et al.Clinical application of whole-exome sequencing across clinical indications.Genet. Med. 2016; 18: 696-704Abstract Full Text Full Text PDF PubMed Scopus (586) Google Scholar The general assertion criteria for variant classification can be found in Table S1. For subject 9, identified by communication with another testing laboratory (K.W., unpublished data), trio exome sequencing was performed on a Novaseq6500 platform (Illumina) in a CLIA certified laboratory (Gene by Gene) via the Agilent SureSelect Clinical Research Exome Capture Enrichment kit (Agilent Technologies) to capture the protein-coding regions. Mapping of the obtained reads to the reference genome (build GRCh37/hg19), variant calling, annotation, and data analysis were done with the Genoox data analysis platform. Variants were prioritized on the basis of their effect on the protein (missense, nonsense, frameshift, splice-site) and their having a minor allele frequency below 1% in general population databases, such as gnomAD,12Lek M. Karczewski K.J. Minikel E.V. Samocha K.E. Banks E. Fennell T. O’Donnell-Luria A.H. Ware J.S. Hill A.J. Cummings B.B. et al.Exome Aggregation ConsortiumAnalysis of protein-coding genetic variation in 60,706 humans.Nature. 2016; 536: 285-291Crossref PubMed Scopus (6555) Google Scholar the Greater Middle East Variome, and the Rambam Genetics Institute internal database of over 1,500 Israeli exomes. All variants were confirmed by Sanger sequencing and reported with the NM_001303256.1 transcript of MORC2 (Figure S1). We identified nine missense variants clustering in the ATPase module of MORC2 (Tables 1 and S1, Figure 1). None of these variants are reported in gnomAD,12Lek M. Karczewski K.J. Minikel E.V. Samocha K.E. Banks E. Fennell T. O’Donnell-Luria A.H. Ware J.S. Hill A.J. Cummings B.B. et al.Exome Aggregation ConsortiumAnalysis of protein-coding genetic variation in 60,706 humans.Nature. 2016; 536: 285-291Crossref PubMed Scopus (6555) Google Scholar and all were considered to be pathogenic or likely pathogenic in the context of the 2015 American College of Medical Genetics and Genomics (ACMG) standards and guidelines for the interpretation of sequence variants (Table S1).13Richards S. Aziz N. Bale S. Bick D. Das S. Gastier-Foster J. Grody W.W. Hegde M. Lyon E. Spector E. et al.ACMG Laboratory Quality Assurance CommitteeStandards and guidelines for the interpretation of sequence variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology.Genet. Med. 2015; 17: 405-424Abstract Full Text Full Text PDF PubMed Scopus (14622) Google Scholar To our knowledge, five (55.6%) of the variants were previously unreported. Published individuals for whom clinical information was available were included in Table 1 for comparison.Table 1Detailed Clinical Description of Individuals with Variants in the ATPase module of MORC2Affected IndividualMutationInheritanceSexAge at ExaminationGrowth Parameters (Z Scores)aReported as standard deviations (SDs) of the raw Z score from the mean based on CDC standards.Cognitive and DevelopmentFacial DysmorphismHearing LossEndocrineNeuromuscular FeaturesEMG/NCSBrain MRIOther FeaturesAdditional Variants ReportedHeightWeightHCMotor DelaySpeech DelayIntellectual DisabilitySubject 1Thr24Ilede novofemale4.2 years−3.41−2.95−3.72++mild+−precocious pubertyhigh arches, hyperreflexia, spasticity, ataxic and jerking movements of arms and legs, thoracic kyphosis; only walks with a walkernormalabnormal T2 hyperintensity in right cerebral peduncle, cortical atrophy with ventriculomegaly, abnormal signal in right putamen and diffuse, ill-defined white matter hyperintensitystrabismusN/ASubject 2Glu27Lysde novomale17 years−3.66−5.6−2.05++mild−−delayed puberty, growth hormone deficiency, hypothyroidismhigh arches, toe walking, spasticity, hyperreflexiaN/Anormal at age 14 yearsN/AN/ASubject 3Glu27Lysde novofemale4.8 years−3.13−2.36−5.03++moderate+−vitamin D deficiencyhigh arches, hyporeflexia in lower extremitiesN/Asevere delay in myelination with T2 hyperintensity in the substantia nigra, mild cerebral atrophysevere GERD, hyperopia, ptosis, capillary hemangiomac.81dupG in COX14, heterozygous (LPATH); p.Leu368Arg in DHTKD1, heterozygous (VUS)Subject 4Glu27Lysde novomale26.6 years−3.28−2.91−0.94++mild+SNHL, severe, hearing aid in one ear and a cochlear implant in the otherprecocious puberty, mildly increased prolactinhyporeflexia, reduced range of motion in large joints, knee contractures, crouched and stiff gaitnormalnormal at age 12 yearssalt and pepper maculopathy, strabismus, oromotor dyspraxia, constipation, autismm.3397A>G, homoplasmic (VUS)Subject 5Glu27Lysunknownfemale5.5 years−2.890.4−4.02++severe−mixed, moderate-profound, hearing aids−hypotonia, weakness, hyperreflexiaN/Aventriculomegaly, supratentorial and infratentorial volume loss with diffusely abnormal white matter and prominent cavitary encephalomalacia in the putamina and caudate headsretinal dystrophy on ERG, bilateral ptosis, esotropia, epilepsy, GERD, feeding difficulties, laryngomalacia, sialorrhea, history of acute respiratory failure with illness, neutropenia, lactic acidosisN/ASubject 6Glu27Lysde novofemale1.3 years−1.58−0.93−1.35++N/A+−−axial hypotonia, appendicular hypertonia (more pronounced in the lower extremities), hyperreflexia and extensor plantar responseN/Anormal at 10 monthsnon-specific peripheral retinal depositsN/ASubject 7Ser87Leude novomale4.8 years−2.32−2.58−0.4++severe+−−hypotonia, decreased muscle bulk, proximal weakness, areflexia, non-ambulatorysensory motor axonal neuropathyT2 hyperintensities of the central tegmental tract and superior cerebral peduncles, globus palladi, subthalamic nucleus and substantia nigraunprovoked episodic deterioration in neurologic symptoms, followed by gradual recovery, frequent respiratory infectionsN/ASubject 8Ser87Leude novomale5 years−3.34−4.08−3.46++mild-to-moderate−−−weakness, decreased muscle bulk, mildly elevated creatine kinase, areflexia, wide based and waddling gait, uses a walker and braces for ambulation, mild kyphosisaxonal motor neuropathynormal at 15 monthsproximally placed thumbs, hirsutismN/AHyun et al.14Hyun Y.S. Hong Y.B. Choi B.O. Chung K.W. Clinico-genetics in Korean Charcot-Marie-Tooth disease type 2Z with MORC2 mutations.Brain. 2016; 139: e40Crossref PubMed Scopus (21) Google ScholarSer87Leude novomale13 yearsN/AN/AN/A+N/AN/AN/A+N/Ahypotonia, weakness, areflexia, scoliosis, wheelchair boundsensory motor neuropathynormalN/AN/ASer87Leude novofemale10 yearsN/AN/AN/A+N/AN/A+N/AN/Ahypotonia, weakness, areflexia, scoliosis, wheelchair boundsensory motor neuropathynormalcataractN/ASevilla et al.4Sevilla T. Lupo V. Martínez-Rubio D. Sancho P. Sivera R. Chumillas M.J. García-Romero M. Pascual-Pascual S.I. Muelas N. Dopazo J. et al.Mutations in the MORC2 gene cause axonal Charcot-Marie-Tooth disease.Brain. 2016; 139: 62-72Crossref PubMed Scopus (58) Google ScholarSer87Leuunknownfemale1.6 yearsN/AN/A( right), muscle atrophy, foot drop, areflexia, ataxia, uses walker or wheelchair for ambulationsensory motor neuropathygeneralized brain atrophy and scattered subcortical and deep white matter microangiopathic changes disproportionate to patient’s ageessential thrombocytosis, grooved tongue, mildly elevated creatine kinase (500–900 U/L)N/AAndo et al.5Ando M. Okamoto Y. Yoshimura A. Yuan J.H. Hiramatsu Y. Higuchi Y. Hashiguchi A. Mitsui J. Ishiura H. Fukumura S. et al.Clinical and mutational spectrum of Charcot-Marie-Tooth disease type 2Z caused by MORC2 variants in Japan.Eur. J. Neurol. 2017; 24: 1274-1282Crossref PubMed Scopus (24) Google ScholarTyr394Cysunknownmale29 yearsN/AN/AN/A−−−N/AN/AN/Ahyporeflexia, gait abnormalities, weakness, distal atrophysensory neuropathyN/AN/AN/ASubject 19Val413Phematernalfemale5.6 years−2.29−2.350.09++mild+−growth hormone deficiencyhypotonia, weakness, hyporeflexia, ataxia, action tremorN/Anormal at age 3 yearsduplicated collecting systemp.Leu2127Pro in ASXL3, heterozygous, maternal (VUS)Subject 20Val413Pheunknownfemale29 years−2.20.52−2.33++mild+hearing loss, type unknowngrowth hormone deficiencytingling in extremities with onset in 20 sN/AN/AN/Ap.Leu2127Pro in ASXL3, heterozygous (VUS)Abbreviations are as follows: EMG, electromyogram; NCS, nerve conduction study; MRI, magnetic resonance imaging; SNHL, sensorineural hearing loss; ERG, electroretinography; GERD, gastresophageal reflux; N/A, not available; LPATH, likely pathogenic; PATH, pathogenic; VUS, variant of uncertain significance.a Reported as standard deviations (SDs) of the raw Z score from the mean based on CDC standards.b Z scores or raw numbers not available in the publication. Open table in a new tab Abbreviations are as follows: EMG, electromyogram; NCS, nerve conduction study; MRI, magnetic resonance imaging; SNHL, sensorineural hearing loss; ERG, electroretinography; GERD, gastresophageal reflux; N/A, not available; LPATH, likely pathogenic; PATH, pathogenic; VUS, variant of uncertain significance. Our cohort includes a diverse group of individuals; 12/20 (60%) were female, and the average age at the time of last examination was 14.2 years (range 1.3–49 years). The primary indication for genetic testing was developmental delay or growth failure, with the exception of the oldest individual (Subject 18) who presented with a diagnosis of sensorimotor neuropathy. The most commonly described features include gross motor delay (19/20, 95%), short stature (height < 2 SDs from the mean for age, 18/20, 90%), intellectual disability (18/20, 90%), and microcephaly (head circumference < 2 SDs from the mean for age, 15/20, 75%) (Tables 1 and 2). Facial dysmorphism was reported in 16/20 (80%) individuals, but the features were subtle and variable. Facial characteristics often consist of a long face with a narrow jaw, deep set eyes, broad nasal tip, thin upper lip, dental crowding, and high palate (Figure 2). Gait abnormalities were reported in 15/16 (94%) individuals; hypotonia (11/16, 69%) and decreased or absent deep tendon reflexes (DTRs; 9/18, 50%) were also commonly noted. Ten individuals had nerve conduction studies (NCSs); four of them reportedly had normal testing, whereas six showed sensorimotor peripheral neuropathy. Hearing loss was reported in 11/19 (58%) and was progressive; two individuals received cochlear implants (subjects 4 and 15) and two more use hearing aids (subjects 5 and 13). Pigmentary retinopathy was reported in 5/6 (83%) individuals who had dilated eye exams. Eighteen individuals had a magnetic resonance imaging (MRI) of the brain, which was abnormal in 12 individuals (66%). Reported changes included Leigh syndrome-like lesions (symmetric abnormalities in the brainstem, basal ganglia, or cerebellum) in five of those 18 individuals. A diagnosis of mitochondrial disease was suspected in seven individuals (subjects 1, 3, 4, 5, 7, 10, and 12).Table 2Summary of Clinical Characteristics of Individuals with Variants in the ATPase Module of MORC2This PaperAll IndividualsClinical CharacteristicsTotal%Total%Short staturea2 standard deviations (SDs) below the mean for age by CDC standards.18/209018/2090Microcephalya2 standard deviations (SDs) below the mean for age by CDC standards.15/207516/2176Developmental DelayMotor delay19/209522/2396Intellectual disability18/209018/2282Facial dysmorphism16/208017/2181Hearing Loss11/195812/2060Pigmentary retinopathy5/6835/683NeuromuscularHypotonia11/166914/1974Hyporeflexia/areflexia9/185013/2259Hyperreflexia6/18336/2227Weakness8/155312/1963High arches7/16447/1644Gait abnormalities15/169418/1995EMG/NCS abnormalities6/106011/1573Brain MRIAny abnormality12/186612/2157Leigh-like lesionsbBased on ClinGen panel Leigh syndrome curation guidelines.5/18285/2124White matter abnormalities9/18509/2143Abbreviations are as follows: EMG, electromyogram; NCS, nerve conduction study; MRI, magnetic resonance imaginga 2 standard deviations (SDs) below the mean for age by CDC standards.b Based on ClinGen panel Leigh syndrome curation guidelines. Open table in a new tab Abbreviations are as follows: EMG, electromyogram; NCS, nerve conduction study; MRI, magnetic resonance imaging The recurrent variants present in our cohort, c.79G>A (p.Glu27Lys), c.260C>T (p.Ser87Leu), c.394C>T (p.Arg132Cys), and c.1181A>G (p.Tyr394Cys), have been previously reported in the medical literature.4Sevilla T. Lupo V. Martínez-Rubio D. Sancho P. Sivera R. Chumillas M.J. García-Romero M. Pascual-Pascual S.I. Muelas N. Dopazo J. et al.Mutations in the MORC2 gene cause axonal Charcot-Marie-Tooth disease.Brain. 2016; 139: 62-72Crossref PubMed Scopus (58) Google Scholar,5Ando M. Okamoto Y. Yoshimura A. Yuan J.H. Hiramatsu Y. Higuchi Y. Hashiguchi A. Mitsui J. Ishiura H. Fukumura S. et al.Clinical and mutational spectrum of Charcot-Marie-Tooth disease type 2Z caused by MORC2 variants in Japan.Eur. J. Neurol. 2017; 24: 1274-1282Crossref PubMed Scopus (24) Google Scholar,14Hyun Y.S. Hong Y.B. Choi B.O. Chung K.W. Clinico-genetics in Korean Charcot-Marie-Tooth disease type 2Z with MORC2 mutations.Brain. 2016; 139: e40Crossref PubMed Scopus (21) Google Scholar,16Deciphering Developmental Disorders StudyPrevalence and architecture of de novo mutations in developmental disorders.Nature. 2017; 542: 433-438Crossref PubMed Scopus (765) Google Scholar Clinical findings among individuals harboring the same variant were assessed (Table 1). Five subjects (subjects 2–6) were heterozygous for c.79G>A (p.Glu27Lys). This variant was previously reported de novo in a child with developmental delay by the Deciphering Developmental Disorders Study group,16Deciphering Developmental Disorders StudyPrevalence and architecture of de novo mutations in developmental disorders.Nature. 2017; 542: 433-438Crossref PubMed Scopus (765) Google Scholar but detailed clinical information was not available. Developmental delay, intellectual disability, and microcephaly were reported in four individuals. Subject 6 was referred for evaluation of declining growth parameters, but at the time of her last assessment, her head circumference was in the normal range (1.35 SDs below the mean) and she was too young to have her intellectual abilities assessed. Two of our subjects required hearing aids at age 5 and 10 years, and further progression required a unilateral cochlear implant at age 13 years in one of them. Brain MRI shows abnormalities of the white matter, basal ganglia, and cerebral atrophy in two individuals, while three others were normal at ages 10 months, 12 years, and 14 years. NCSs were normal in one individual but were not performed in the others. In addition, subject 6 has non-specific peripheral retinal deposits at age 1 year, and two other individuals, the youngest at age 5 years, have clear pigmentary retinopathy. Subject 5 also harbors a pathogenic copy number gain of approximately 3 Mb at chromosome 22q11.21, a contiguous gene duplication (MIM: 608363) with a highly variable phenotype ranging from asymptomatic to severe developmental delay, short stature, hearing loss, and hypotonia, which could be contributing to her presentation. Characteristic brain MRI findings and retinal changes have not been described with this chromosomal abnormality. Two subjects (subjects 7 and 8) harbored the c.260C>T (p.Ser87Leu) variant. Both have muscular weakness, areflexia, and gait impairment; neurophysiologic studies confirmed a sensorimotor neuropathy in each individual. Subject 7 experienced two apparently unprovoked regressions in symptoms, first with worsening hypotonia, weakness, and loss of babbling at age 9 months and again with worsening truncal hypotonia at 33 months; each time was followed by a plateau and slow improvement. He has developmental delay and severe intellectual disability, and his head circumference is normal (Z score = −0.40), but a brain MRI shows brain stem and basal ganglia abnormalities that did not change on repeat imaging at 10 months and 34 months. Subject 8 has decreased muscle bulk and mildly elevated serum creatine kinase activity; exome sequencing also showed a de novo, likely pathogenic variant in MYH7 (MIM: 160760) associated with autosomal-dominant myopathies and cardiomyopathy that could be responsible for those features and contribute to the weakness and areflexia but would not explain the growth abnormalities or intellectual disability. The c.260C>T (p.Ser87Leu) variant in MORC2 has been reported in several children considered to have infantile onset CMT disease type 2Z.4Sevilla T. Lupo V. Martínez-Rubio D. Sancho P. Sivera R. Chumillas M.J. García-Romero M. Pascual-Pascual S.I. Muelas N. Dopazo J. et al.Mutations in the MORC2
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