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1 Novel biallelic variants in MSTO1 associated with mitochondrial myopathy
2
3 Laura Schultz-Rogers1, Alejandro Ferrer1, Nikita R. Dsouza2, Michael T. Zimmermann2,3, Benn
4 E. Smith4, Eric W. Klee1,5, Radhika Dhamija6
5
6 1Center for Individualized Medicine, Mayo Clinic, Rochester, MN, 55905 USA
7 2Bioinformatics Research and Development Laboratory, Genomics Sciences and Precision
8 Medicine Center, Medical College of Wisconsin, Milwaukee, WI 53226, USA
9 3Clinical and Translational Sciences Institute, Medical College of Wisconsin, Milwaukee, WI
10 53226, USA
11 4Department of Neurology, Mayo Clinic, Scottsdale, AZ, 85259 USA
12 5Department of Clinical Genomics, Mayo Clinic, Rochester, MN, 55905 USA
13 6Department of Medical Genetics, Mayo Clinic, Phoenix, AZ, 85054 USA
14 Corresponding author’s email: [email protected]
15
16 HPO TERMS:
17 Hypotonia, early HP:0008947; Restrictive lung disease HP:0002091; Elevated creatine kinase
18 HP:0003236; Delayed gross motor development HP:0002194; Speech articulation difficulties
19 HP:0009088; Dysphagia HP:0002015; Waddling gait HP:0002515; Pectus excavatum
20 HP:0000767; Lumbar kyphosis HP:0008454; EMG: myopathic abnormalities HP:0003458
21
22 SHORT RUNNING TITLE: Novel biallelic variants in MSTO1 myopathy
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24
25
26 Downloaded from molecularcasestudies.cshlp.org on September 28, 2021 - Published by Cold Spring Harbor Laboratory Press
27 ABSTRACT
28 Mitochondrial disorders are caused by nuclear and mitochondrial pathogenic variants
29 leading to defects in mitochondrial function and cellular respiration. Recently, the nuclear-
30 encoded mitochondrial fusion gene MSTO1 (Misato 1) has been implicated in mitochondrial
31 myopathy and ataxia. Here we report on a 30 year old man presenting with a maternally
32 inherited NM_018116.3:c.651C>G, p.F217L missense variant as well as a paternally inherited
33 arr[GRCh37] 1q22(155581773_155706887)x1 deletion encompassing exons 7-14 of MSTO1.
34 His phenotype included muscle weakness, hypotonia, early motor developmental delay, pectus
35 excavatum, and scoliosis. Testing revealed elevated plasma creatine kinase, and
36 electromyogram results were consistent with longstanding generalized myopathy. These
37 phenotypic features overlap well with previously reported patients harboring biallelic MSTO1
38 variants. Additionally, our patient presents with dysphagia and restrictive lung disease, not
39 previously reported for MSTO1-associated disorders. The majority of patients with disease
40 associated variants in MSTO1 present with biallelic variants suggesting autosomal recessive
41 inheritance, however one family has been reported with a single variant and presumed
42 autosomal dominant inheritance. The pattern of inheritance we observed is consistent with the
43 majority of previous reports suggesting an autosomal recessive disorder. We add to our
44 knowledge of the syndrome caused by variants in MSTO1 and provide additional evidence
45 supporting autosomal recessive inheritance. We also describe phenotypic features not reported
46 in previous cases, although further research is needed to confirm they are associated with
47 defects in MSTO1.
48
49 INTRODUCTION
50 Mitochondrial dysfunction leads to a diverse array of disorders most often characterized
51 by myopathic and neurologic symptoms (Chinnery 1993). As the mitochondria are essential for
52 normal aerobic metabolism, tissues and organs with high energy demands such as skeletal Downloaded from molecularcasestudies.cshlp.org on September 28, 2021 - Published by Cold Spring Harbor Laboratory Press
53 muscle are particularly sensitive to mitochondrial disruption (Wallace 1999). Damaging variants
54 in over 1000 nuclear encoded and mitochondrial genes can affect respiratory chain complexes,
55 mtDNA replication and maintenance, and dynamic fusion and fission processes. Fusion helps
56 maintain a healthy population of mitochondria by distributing mtDNA and metabolites and
57 eliminating damaged mitochondria through mitophagy (for review see (El-Hattab et al. 2018)).
58 MSTO1 (Misato 1) is a nuclear gene that contains a region homologous to the
59 Tubulin/FtsZ, GTPase superfamily which contains proteins that regulate chromosome
60 segregation in eukaryotes and mitochondrial fission in eukaryotic algae (Kimura and Okano
61 2007). It encodes a soluble cytoplasmic protein that translocates to the mitochondrial outer
62 membrane and promotes normal fusion dynamics (Kimura and Okano 2007; El-Hattab et al.
63 2018; Nasca et al. 2017; Gal et al. 2017). In drosophila knockdown of DML1, the homolog of
64 human MSTO1, leads to defects in chromosome segregation during mitosis (Miklos et al. 1997).
65 In S. cerevisiae, disruption of DML1 causes impaired inheritance of mtDNA and segregation of
66 mitochondria (Gurvitz et al. 2002). Inhibition of MSTO1 in HeLa cells results in nuclear and
67 mitochondrial fragmentation, reduced fusion, and apoptosis, while overexpression results in
68 perinuclear aggregations of mitochondria (Kimura and Okano 2007; Gal et al. 2017).
69 MSTO1 was first associated with human disease in 2017 when Nasca et al. reported on
70 three patients with compound heterozygous variants in MSTO1 presenting with myopathy and
71 cerebellar ataxia (MIM:617675). Functional studies in patient fibroblasts confirmed partially
72 reduced transcript and protein expression as well as fragmentation of the mitochondrial network
73 and decreased mitochondrial fusion (Nasca et al. 2017). To date, a total of 11 patients have
74 been reported in the literature with myopathy and ataxia attributed to pathogenic variants in
75 MSTO1. Consistent phenotypic features observed across patients include onset in the first year
76 of life, severe motor delay, cerebral atrophy on MRI, short stature, myopathic pattern on EMG,
77 and elevated plasma creatine kinase (CK) (Nasca et al. 2017; Iwama et al. 2018; Li, Jin, and Downloaded from molecularcasestudies.cshlp.org on September 28, 2021 - Published by Cold Spring Harbor Laboratory Press
78 Wu 2019)(Table 1). Additionally, several patients presented with cognitive deficiencies, skeletal
79 abnormalities, tremors, and retinopathy.
80 Here we present a 30 year old male with phenotypic features consistent with previously
81 reported MSTO1 patients. We report additional phenotypic features seen in our patient including
82 dysphagia and restrictive lung disease which may be the consequence of the associated
83 myopathy. Our patient has a novel partial gene deletion adding to the spectrum of variants
84 associated with MSTO1-associated mitochondrial myopathy.
85
86 RESULTS
87 Clinical Presentation
88 A 30 year old Caucasian male presented with moderate-to-severe proximal and distal
89 muscle weakness and significantly decreased muscle tone. He had congenital hypotonia with
90 poor head control and was diagnosed with “muscular dystrophy of unknown type” at 18 months
91 of age. His gross and fine motor milestones were significantly delayed, including walking at 26
92 months of age and the inability to pedal a bike or run as a child. Learning disability was noted at
93 early childhood. Neurological examination at age 30 was significant for proximal and distal
94 muscle weakness with hypotonia, mild facial weakness with ptosis, diminished muscle bulk, no
95 sensory deficits and preserved muscle reflexes. Gait was wide based and waddling. Swallowing
96 video fluoroscopy revealed mild oropharyngeal dysphagia. Electromyogram (EMG) results were
97 consistent with a longstanding, generalized myopathy, with electrodiagnostic features that would
98 predict fiber splitting, necrosis, inflammation, or vacuolar change. He has persistently elevated
99 CK levels with titers between 1000 and 2000 U/L. Pulmonary function tests showed a chronic
100 restrictive pattern with Forced Vital Capacity (FVC) at 44-49% of predicted leading to a
101 diagnosis of restrictive lung disease (Figure 1A,B).
102 Additional phenotypic features reported in the patient include pectus excavatum that was
103 surgically corrected at age 18, as well as scoliosis characterized by mild reversal of cervical Downloaded from molecularcasestudies.cshlp.org on September 28, 2021 - Published by Cold Spring Harbor Laboratory Press
104 lordosis and a trace gentle convex curvature of the lumbar spine to the right (Figure 1C,D). An
105 echocardiogram was normal. The family history was unremarkable with the exception of a
106 maternal grandmother who died of complication from ALS at age 74 (Figure 2).
107
108 Genomic Analysis
109 Initial genetic testing included a 141 gene panel (Neuromuscular Genetics Panel; Mayo
110 Clinic) and dystrophin deletion/duplication sequencing analysis. None of the variants reported
111 were considered relevant (Table 2). Testing for Pompe’s disease was also negative.
112 Mitochondrial DNA NGS testing was performed through GeneDX, and a homoplasmic variant of
113 uncertain significance (m.8045A>G, p.I154V) was reported in MT-CO2. This variant was also
114 considered not diagnostic as the patient’s unaffected mother was homoplasmic for the same
115 variant. Whole exome sequencing performed through GeneDx reported two potentially clinically
116 relevant variants; a maternally inherited NM_018116.3:c.651C>G, p.F217L missense variant of
117 uncertain significance and a likely pathogenic paternally inherited arr[GRCh37]
118 1q22(155581773_155706887)x1 copy number change (Figure 3A). The copy number change
119 was originally detected through GeneDx’s NGS-CNV caller (Retterer et al. 2015) and was
120 confirmed by GeneDx with the GenomeDx v5 chromosomal array. The missense variant was
121 confirmed by GeneDx via direct gene-specific PCR.
122 The p.F217L missense variant lies in exon 7 of 14 in the tubulin domain. The affected
123 amino acid is highly conserved across species (Figure 3B) and in silico predictions agree the
124 variant is likely damaging (Polyphen-2 (Adzhubei et al. 2010), SIFT (Sim et al. 2012), M-CAP
125 (Jagadeesh et al. 2016), PredictSNP2 (Bendl et al. 2016)). The p.F217Lvariant could possibly
126 affect the structural conformation as it is a part of an alpha helix and the only hydrophobic
127 residue within a region of charged and hydrophilic residues. The
128 1q22(155581773_155706887x1) copy number variant is a 125 kb deletion encompassing exons
129 7-14 of MSTO1, exon 7-13 of the MSTO2P pseudogene, and all of DAP3 (death associated Downloaded from molecularcasestudies.cshlp.org on September 28, 2021 - Published by Cold Spring Harbor Laboratory Press
130 protein 3) and YY1AP1 (YY1 associated protein 1). While the homology between MSTO1 and
131 its pseudogene could affect the detection of CNV’s in this gene, the fact that the missense
132 variant in exon 7 was called as homozygous supports the presence of a deletion in this gene.
133 MSTO2P is not associated with any human disorders other than potential links to cancer, not
134 reported in our patient. Biallelic loss of function variants in YY1AP1 are associated with Grange
135 syndrome, while missense and small insertion variants in DAP3 have been associated with
136 metabolic disorders and autism spectrum disorder. Since our patient does not have a second
137 damaging variant reported in these genes and his phenotype does not overlap with these
138 syndromes, we concluded that it is not likely that a single copy loss of any of these three genes
139 is contributing to our patient’s phenotype.
140 MSTO1 is not predicted to be intolerant to loss of function or missense variation based
141 on gene constraints in gnomAD (pLI=0, Z=0) (Lek et al. 2016). However, as autosomal
142 recessive inheritance is expected it is possible to see damaging variants in a heterozygous state
143 in the normal population. The p.F217L variant is observed at a very low frequency in gnomAD
144 (0.007%) with no homozygotes reported. This variant has not been previously reported in
145 HGMD or ClinVar. The 1q22(155581773_155706887) deletion has not been previously
146 observed in normal or diseased individuals. Based on the Database of Genomic Variants
147 similarly sized deletions have been detected in heterozygotes in the normal population
148 (nsv436522, nsv3043, nsv48213)(MacDonald et al. 2014).
149
150 DISCUSSION
151 Here we present a patient with novel compound heterozygous variants in MSTO1 and
152 mitochondrial myopathy. His phenotypic presentation overlaps well with previously reported
153 patients including early onset muscle weakness, motor delay, elevated plasma CK, myopathic
154 pattern on EMG, and skeletal abnormalities. At 30 years old, our patient is the oldest reported
155 patient with biallelic variants in MSTO1, adding important knowledge about potential lifespan for Downloaded from molecularcasestudies.cshlp.org on September 28, 2021 - Published by Cold Spring Harbor Laboratory Press
156 other similarly affected patients. We report features including restrictive lung disease and
157 dysphagia not previously identified in patients with MSTO1-associated mitochondrial myopathy.
158 These additional clinical findings may be the consequence of the associated myopathy.
159 Awareness of the full phenotypic spectrum associated with this disorder is critical for proper
160 diagnosis of future patients. As the role of tubulins in mitochondrial function becomes more
161 apparent (Mado et al. 2019), it will be important to elucidate the role of MSTO1 in normal
162 mitochondrial dynamics and how disruption leads to myopathy as well as skeletal, retinal, and
163 other phenotypic features observed.
164 The p.F217L missense variant seen in our patient lies in the second tubulin domain on
165 the MSTO1 protein. Five of the six previously reported pathogenic missense variants lie in one
166 of the tubulin domains, suggesting these regions are critical for normal protein function and/or
167 stability. Regions of proteins that bind to other proteins often have a hydrophobic center with a
168 hydrophilic and charged ring surrounding them, much like the region around p.F217. If protein
169 interactions with the MSTO1 tubulin domain occur at p.F217, then p.L217 may be compatible
170 with the overall pattern of protein interfaces, but with a reduced and smaller hydrophobic center,
171 which may not be as specific for its binding partners.
172 Similar to our patient, five of the eleven previously reported patients were compound
173 heterozygotes with one missense variant and one loss of function variant (Figure 3A). The two
174 most severely affected patients were compound heterozygotes for two missense variants.
175 Nasca et al. hypothesized that the reduction in protein expression in these patients was due to
176 instability caused by the missense variants. In the gnomAD database of healthy individuals
177 there is only one individual reported as homozygous for any loss of function allele and this call
178 was flagged as dubious. This suggests that MSTO1 is associated with disease in an autosomal
179 recessive manner wherein biallelic loss of function variants are likely lethal but retention of a
180 partially functional missense allele in conjunction with a loss of function allele results in a
181 disease state. This is supported by studies in drosophila in which null mutations are embryonic Downloaded from molecularcasestudies.cshlp.org on September 28, 2021 - Published by Cold Spring Harbor Laboratory Press
182 lethal (Miklos et al. 1997). Here we present an additional patient with a loss of function variant,
183 in this case a partial gene deletion, in combination with a missense variant in MSTO1 resulting
184 in mitochondrial myopathy.
185 Contrary to the other reported cases, Gal et al. reported a heterozygous missense
186 variant in members of a family presenting with myopathy, ataxia, and neurodevelopmental
187 impairments (Gal et al. 2017). A second alteration in MSTO1 was not detected with Sanger
188 sequencing of the genomic DNA or real-time PCR analysis of copy number variation. The
189 authors proposed autosomal dominant inheritance of a multi-systemic clinical phenotype.
190 However, the phenotypic features in this family do not overlap well with other reported patients
191 (Table 1). In particular, age of onset was later (15-53 years old), plasma CK levels were normal,
192 and cerebellar atrophy was not observed. Functional studies in fibroblasts from patients 1 and 2
193 (as labeled in the Gal et al. study) did confirm a decrease in transcript and protein expression,
194 mitochondrial fusion, and fragmented and aggregated mitochondria. These discrepant reports
195 may be explained by a genotype/phenotype correlation in which the mode of inheritance
196 depends on the location of the variant or a separate underlying genetic condition.
197 This case adds to our current knowledge on mitochondrial myopathy associated with
198 biallelic pathogenic variants in MSTO1. We present novel phenotypic features not previously
199 described in association with MSTO1-related disease, and add support to reports of autosomal
200 recessive inheritance. We expect that additional MSTO1 cases and further research will
201 elucidate the full clinical spectrum of this disorder.
202
203 METHODS
204 Whole exome sequencing was performed by GeneDx. The mean depth of coverage was 157x
205 and the quality threshold (percentage of sequence covered by at least 10 reads) was 98.9%.
206 Briefly, a proprietary capture system was used for next-generation sequencing and targets were
207 sequenced with paired-end reads on an Illumina platform. Reads were aligned to Downloaded from molecularcasestudies.cshlp.org on September 28, 2021 - Published by Cold Spring Harbor Laboratory Press
208 GRCH37/UCSC hg 19. Sequence variants and deletions or duplications involving three or more
209 coding exons were called with XomeAnalyzer. Variants were reported according to the Human
210 Genome Variation Society (HGVS) guidelines. Missense variants were clinically confirmed with
211 direct gene-specific PCR. Copy number variants were clinically confirmed by chromosomal
212 microarray. Briefly, the GeneDx GenomeDx v5 chromosomal array contains 118,000
213 oligonucleotide probes and 66,000 SNP probes throughout the genome used for detecting copy
214 number variants.
215 Sequencing Coverage:
Mean Depth of Coverage 157x
Quality Threshold 98.9%
216
217 As a separate test from whole exome sequencing, mitochondrial sequencing and
218 deletion testing of the mitochondrial genome was performed by GeneDx. Briefly, the
219 mitochondrial genome was amplified and sequenced using a solid state sequencing by-
220 synthesis process and the sequence was compared to the revised Cambridge Reference
221 Sequence (rCRS). Disease associated variants were confirmed by conventional dideoxy
222 sequence analysis.
223
224 ADDITIONAL INFORMATION
225 Data Deposition and Access— Single nucleotide variants identified and interpreted by
226 GeneDx can be found in the ClinVar database (accession number SCV000965685).
227 Ethics Statement— This study was approved by the Mayo Clinic institutional review board and
228 all participants provided written informed consent for genetic testing.
229 Acknowledgments – We would like to thank the patient and his family for participating in this
230 study. Downloaded from molecularcasestudies.cshlp.org on September 28, 2021 - Published by Cold Spring Harbor Laboratory Press
231 Author Contributions— L.S.R, A.F., and E.W.K. analyzed patient variants and wrote
232 manuscript. R.D. and B.S. oversaw patient care and genetic interpretation. N.R.D. and M.T.Z.
233 interpreted protein structure. All authors reviewed and approved the final manuscript.
234 Funding - This study was supported by the Mayo Clinic Center for Individualized Medicine.
235
236 REFERENCES
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299
300 FIGURE LEGENDS
301 Table 1. Phenotypic spectrum of MSTO1-associated myopathy. Comparisons of variants,
302 inheritance, and phenotypic features seen across all currently reported patients with MSTO1-
303 associated mitochondrial myopathy. n/a = not available.
304
305 Table 2. Discarded variants of uncertain significance. Prior to whole exome sequencing, a
306 141 gene Neuromuscular Genetics Panel was performed on patient DNA. Several variants of
307 uncertain significance were reported, but all were discarded as candidates for the reasons
308 described in the table.
309 Downloaded from molecularcasestudies.cshlp.org on September 28, 2021 - Published by Cold Spring Harbor Laboratory Press
310 Figure 1. Pulmonary function and skeletal abnormalities in a patient with biallelelic
311 MSTO1 variants. A) Air flow (Liters per second) vs. volume (L) displays severe restriction of
312 pulmonary function. B) The forced expiratory volume in one second (FEV1)/forced vital capacity
313 (FVC) is normal; the FEV1 is moderately to severely reduced; the FVC is reduced; maximal
314 expiratory pressure (MEP) 24% predicted, maximal inspiratory pressure (MIP) 38% predicted.
315 Overall results of the pulmonary function test confirm a chronic restrictive pattern. C) Skeletal
316 radiographs show mild reversal of cervical lordosis and D) trace gentle convex curvature of the
317 lumbar spine to the right.
318
319 Figure 2. Family pedigree. A three generation family pedigree in which the proband is the only
320 affected individual. Each MSTO1 variant was inherited from an unaffected parent.
321
322 Figure 3. Gene location of disease associated MSTO1 variants. A) Map of currently known
323 MSTO1 variants associated with mitochondrial myopathy. Green and blue regions denote the
324 tubulin domains. Most of the variants cluster in the known tubulin domains. Figure generated
325 using ProteinPaint, St. Jude Children’s Research Hospital. B) The amino acid affected by our
326 patient’s missense variant (red box) shows high conservation among orthologs.
327
328 TABLES
329 Table 1.
Nasca Nasca Nasca Iwama Iwama Gal Gal Li 2019; Li 2019; Present Gal 2017; Gal 2017; Patient 2017; 2017; 2017; 2018; 2018; 2017; 2017; Patient 1 Patient 2 study Patient 1 Patient 2 Patient 1 Patient 2 Patient 3 Patient 1 Patient 2 Patient 3 Patient 4 Variant c.1033C c.1033C c.971C > c.836 G > c.836 G > c.836G > c.836G > c.651 c.22G > c.22G > 1 c.22G > A c.22G > A > T > T T A A A A C>G A A (cDNA) Variant 1 p.Arg279 p.Arg279 p.Arg279 p.Arg279 p.Val8Me p.Val8Me p.R345C p.R345C p.T324I p.F217L p.Val8Met p.Val8Met (protein His His His His t t ) Variant 1q22 125 c.1128C c.1128C 966+1G c.1099– c. 79 C > c.1259D c.1259D 2 kb None None None None > A > A > A 1 G > A T elG elG (cDNA) deletion Variant n/a p.Val367 p.Gly420 p.Gly420 p.F376L p.F376L p.Gln27* n/a None None None None 2 (splice) Trpfs *2 ValfsTer ValfsTer Downloaded from molecularcasestudies.cshlp.org on September 28, 2021 - Published by Cold Spring Harbor Laboratory Press
(protein 2 2 ) Variant Missense Missense Missense Missense Missense Missense Missense Missense Missense Missense Missense Missense 1 Type Partial Variant Splice Splice Nonsens Frameshi Frameshi Missense Missense gene 2 Type site site e ft ft deletion Inherita AR AR AR AR AR AR AR AR AD AD AD AD nce Early Age of 8-9 8-9 10 Childhoo 1 year 5 months Perinatal 1 year Perinatal 53 years 15 years childhoo onset months months months d onset d Motor Yes Yes Yes Yes Yes Yes Yes Yes Yes No No Yes delay? Frontal atrophy Pituitary Cerebell Cerebell Cerebell Cerebell Cerebell Cerebell and adenoma Brain Cerebella ar ar ar ar ar ar n/a enlarged and mild n/a n/a MRI r atrophy atrophy atrophy atrophy atrophy atrophy atrophy interhemis cerebellar pheric ectopia fissure Growth impair Yes Yes n/a Yes Yes Yes Yes No Yes n/a n/a n/a ment Plasma CK 1200 1872 4520 430 916 n/a 2544 1292 Normal Normal Normal n/a value Tremor Yes Yes Yes Yes Yes No No No No No No No s Speech Develop Cogniti delay, Mild Mild Learning mental Mental Learning Learning ve speech develop develop disability, Developm None None delay, retardatio None difficultie difficultie deficien articulati mental mental speech ental delay slurred n s s cy on delay delay difficulty speech difficulty Bilateral retinal pigmenta Pigmenta Ophthal ry ry Pigmenta mologi Bilateral denaturat Visual retinopat ry retinal cal papillary Normal ion, impairme Myopia No No No No No hy with denaturat finding pallor severe nt papillary ion s hypermet pallor ropia, and esotropia Severe III digit on Bone Pectus asymmetr foot develop excavatu y of the Pes missing, mental Multiple m, Skeletal chest, Asymmet planus bone age problems Laxity of arthrogry Pes reversal abnorm pectus ry of the None None and mild delayed, None , pectus the knee posis, planus of alities excavatu thorax genu joint excavatu joints transient cervical m, and valgus hyperlaxity m, lordosis, marked , pes kyphosco scoliosis scoliosis varus liosis Walked Walkin Able to No Severe at 4 g Unable to Unable walk but walking Able to Able to Waddling Able to episodic Able to Able to years but affecte walk to walk occasion as of 3 walk walk gait walk ataxic gait walk walk loss at d? al falls years repeatedly 13 years Muscle biopsy Yes Yes Yes n/a n/a n/a n/a n/a Yes n/a n/a n/a abnorm alities EMG Myopathi Myopathi Myopathi Myopathi Myopathi Myopathic finding n/a n/a n/a n/a n/a n/a c pattern c pattern c pattern c pattern c pattern pattern s Downloaded from molecularcasestudies.cshlp.org on September 28, 2021 - Published by Cold Spring Harbor Laboratory Press
Depressio n, Hypoacusi Neurolo hallucinati s, anxiety Social gical Autism, ons, Social None None None None None None Autism and anxiety, Disorde anxiety schizophre anxiety depressed autism rs nia, mood hypoacusi s Respira tory None None None None None None None Yes None None None None sympto ms Lipomatosi Inflammat s, Dysphagi ory hyperthyro a, lipomas, idism, Other None None None None None None None restrictiv Hyperthyr None None mitral and e lung eosis, trisucpidal disease hyperprola insufficien ctanemia cy 330 Table 2.
HGVS HGVS DNA Protein Variant Predicted dbSNP/dbVA Gene Chromosome Reference Reference Type Effect R ID Genotype Reason Discarded Lack of phenotypic overlap (no lipodystrophy); no CAVIN1 17:40556955 c.923A>G p.Y308C Missense Substitution rs146799286 Heterozygous second variant found Lack of phenotypic overlap; no second SMCHD1 18:2732423 c.3209T>C p.I1070T Missense Substitution rs113434340 Heterozygous variant found in DUX4 Lack of phenotypic overlap (no cardiovascular TMEM43 3:14177385 c.859C>T p.H287Y Missense Substitution rs780299346 Heterozygous symptoms) Autosomal dominant association with disease but previously reported in unaffected TTN 2:179419690 c.80792T>G p.L26931R Missense Substitution rs72648234 Heterozygous individuals Autosomal dominant association with disease but previously reported in unaffected TTN 2:179587094 c.18688G>A p.A6230T Missense Substitution rs759713604 Heterozygous individuals 331
332 Variant Table:
HGVS Parent Chromosom HGVS DNA Protein Variant Predicted dbSNP/dbVA of Gene e Reference Reference Type Effect R ID Genotype origin
Heterozyg MSTO1 1:155581864 c.651C>G p.Phe217Leu Missense Substitution rs776826330 ous Mother Copy 1q22(155581773 number Partial gene Heterozyg MSTO1 1q22 _155706887)x1 n/a change deletion n/a ous Father 333 Downloaded from molecularcasestudies.cshlp.org on September 28, 2021 - Published by Cold Spring Harbor Laboratory Press
334 FIGURES 335 336 Figure 1:
337 338 Figure 2:
339 340 341 342 Downloaded from molecularcasestudies.cshlp.org on September 28, 2021 - Published by Cold Spring Harbor Laboratory Press
343 Figure 3:
344 Downloaded from molecularcasestudies.cshlp.org on September 28, 2021 - Published by Cold Spring Harbor Laboratory Press
Novel biallelic variants in MSTO1 associated with mitochondrial myopathy
Laura Schultz-Rogers, Alejandro Ferrer, Nikita R. Dsouza, et al.
Cold Spring Harb Mol Case Stud published online October 11, 2019 Access the most recent version at doi:10.1101/mcs.a004309
Published online October 11, 2019 in advance of the full issue.
Accepted Peer-reviewed and accepted for publication but not copyedited or typeset; accepted Manuscript manuscript is likely to differ from the final, published version. Published onlineOctober 11, 2019in advance of the full issue.
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