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Novel contiguous gene deletion in peruvian girl with Trichothiodystrophy type 4 and
glutaric aciduria type 3
PII: S1769-7212(17)30667-5
DOI: 10.1016/j.ejmg.2018.02.004
Reference: EJMG 3421
Please cite this article as: J. La Serna-Infantes, Miguel.Chá. Pastor, M. Trubnykova, Fé.Chavesta.
Velásquez, Flor.Vá. Sotomayor, H.A. Barriga, Novel contiguous gene deletion in peruvian girl with
Trichothiodystrophy type 4 and glutaric aciduria type 3, European Journal of Medical Genetics (2018),
doi: 10.1016/j.ejmg.2018.02.004.
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CLINICAL REPORT
Novel Contiguous Gene Deletion in Peruvian girl with Trichothiodystrophy type 4 and
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1
Department of Cytogenetics y Cytopathology, Hospital Nacional Guillermo Almenara, La
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Victoria Lima, Perú.
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Department of Genetic & Inborn Errors of Metabolism, Instituto Nacional de Salud del
Niño, Breña, Lima, Perú.
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* Correspondence: Hugo Hernán Abarca Barriga, Genetic & Inborn Errors of Metabolism,
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Instituto Nacional de Salud del Niño, Av. Brasil 600, CP Lima 05, Lima, Perú, Phone +51
979301132, habarca@insn.gob.pe
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La Serna-Infantes et al. 2
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ABSTRACT
characterized by dry, brittle, sparse and sulfur-deficient hair and other features like
intellectual disability, ichthyotic skin and short stature, caused by a homozygous mutation in
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MPLKIP gene. Glutaric aciduria type 3 is caused by a homozygous mutation in SUGCT gene
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with no distinctive phenotype. Both genes are localized on chromosome 7 (7p14).
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intellectual disability and hair characterized for dark, short, coarse, sparse and brittle
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showed a 125 kb homozygous pathogenic deletion, which includes genes MPLKIP and
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SUGCT, not described before. This is the first case described in Peru of a novel contiguous
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dry, brittle, sparse, sulfur-deficient hair and other features like intellectual disability,
ichthyotic skin and short stature [Hashimoto & Egly 2009; Pode-Shakked et al. 2015].
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Under polarizing microscopy, the hair displays a classical alternating light and dark
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banding pattern, called “tiger tail banding”, trichorrhexis or trichoschisis, due to thickening or
weak points (nodes) causing easily hair broken [Gummer & Dawber 1985; Hashimoto &
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Egly 2009].
Several acronyms are used to describe patient features: PIBIDS, IBIDS and BIDS for
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Photosensitivity, Ichthyosis, Brittle hair, Intellectual impairment, Decreased fertility, and
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Short stature [Bergmann E. & Egly JM 2017; Faghri, Tamura, Kraemer, & DiGiovanna 2008;
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however, a genetic classification into three groups has also been proposed by Morice-Picard
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Transcription/DNA repair Factor IIH (TFIIH) is affected by mutations of its subunits, causing
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decreased cellular concentrations of the affected protein; ii) non-photosensitive group, which
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includes patients with MPLKIP mutations (Group B-II); iii) and unknown molecular basis
(group B-III) [Morice-Picard et al. 2009; Stefanini M. 2013]. TTD4 belongs to B-II group.
Glutaric aciduria type 3 (GA3, MIM 231690; GARD 12469; ORPHA 35706) is
generally considered a likely "non-disease", caused by mutations in the SUGCT gene, that
decreased conversion of free glutaric acid to glutaryl-coA with no symptoms. It remains less
La Serna-Infantes et al. 4
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well known, characterized and understood than other types of glutaric aciduria [Waters et al.,
2017].
microarray analysis.
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CLINICAL REPORT
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An 8-year-old Peruvian female was born at term by natural birth from young parents
(Father: 24y / Mother: 19y). There were no complications during gestation. Birth weight was
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3500 g. Her parents were apparently unrelated, though the grandparents were originally from
the same small town, located in Cajamarca Region, north of Peru. Family history included a
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paternal uncle with schizophrenia. (Figure 1a). Our patient presented global development
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delay: head control at 8 months, sat with support at 2 years 6 months, walked at 3 years 10
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months and spoke at 4 years. She is currently on first grade at primary school.
Upon examination (8-year-old), her weight was 20 kg (-2.3 SD), height 112 cm (-3.4
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SD), cephalic perimeter 48.6 cm (-3.0 SD) and body mass index 15.9 (-0.17 SD). Her
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phenotype showed: microcephaly, short stature; prematurely aged and asymmetric face with
hypoplasic superciliary / zygomatic arches; scalp, eyebrows and eyelashes hair showed short,
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coarse, sparse and brittle; alopecic parietal area; anteverted nares and thick nasal root,
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downslanding mouth corners; some small ´café au lait´ patches; dental caries and multiple
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teeth decay; follicular keratosis on the back; short, thin and irregular nails of the fingers;
scoliosis, brachydactyly, bilateral clinodactyly of the 5th fingers, flat and valgus feet; normal
muscle tone and deep tendon - plantar reflexes (Figure 1 b – f). Her mental development was
(7p14.1). This deletion contains genes MPLKIP and SUGCT, known to be related to
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Trichothiodystrophy type 4 and Glutaric Aciduria type 3, respectively.
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The mother was heterozygous for the same 7p14.1 deletion detected in the proband
child. Since the mother was a single woman, the father could not be contacted for further
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genetic investigation. The LOH region that contained the described CNV in the proband is
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In order to confirm Glutaric Aciduria type 3 found by CMA, urinary organic acids test
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was performed at Children's Hospital Colorado Laboratory. The results showed increased
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METHODS
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We follow the Ethical Statement regulations of the “Instituto Nacional de Salud del
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Niño” (Lima, Peru) and parental informed written consent was obtained for publication. The
Chromosome Microarray Analysis (CMA) was performed from total DNA (250ng), it was
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amplified, labeled, and hybridized using GeneChip CytoScan 750K Array protocols
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include 550 000 non-polymorphic markers and 200 436 SNP markers. CEL files obtained by
scanning the arrays were analyzed using the Chromosome Analysis Suite (ChAS) software
(Affymetrix, USA). Gains and losses that affected a minimum of 25 markers and LOH
regions that expand over 5Mbp were initially considered (See Thermo Fisher Sc Inc, 2017).
The patient CNVs (Copy Number Variation) were compared with genomic variants in
UCSC) Genome Browser. CNVs were classified as pathogenic, likely pathogenic, and of
unknown clinical significance [Miller et al. 2010; Verma R. & Babu A. 1996].
DISCUSSION
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Nonphotosensitive Trichothiodystrophy 1 (TTDN1), Amish Brittle Hair Brain Syndrome
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(ABHS), Hair-Brain Syndrome, BIDS Syndrome, Pollitt Syndrome or Neurocutaneous-TTD
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phase-specific PLK1-interacting protein) in fewer than 20 percent of all cases. These
mutations do not increase the risk of skin cancer, but they have been found to be associated
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with early mortality, until 20-fold increased risk for death before 10 years [Bergmann E. &
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Egly J.M. 2017; Faghri et al. 2008; Morice-Picard et al. 2009; Stefanini M. 2013].
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MPLKIP gene encodes a nuclear protein which function is not completely known, but
it is thought to interact with polo-like kinase 1 (PLK1), regulating cell cycle and mitosis. It is
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expressed in epidermis, fibroblasts and hair follicles (UniProt: Q8TAP9; NCBI – GTR:
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C1961117). Interactions between cell cycle regulation and transcription efficiency could
explain the TTD phenotype observed in patients with MPLKIP mutations; however, no
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polar mitotic spindles [Cheng & Bayliss 2008; Heller et al. 2015; Morice-Picard et al. 2009;
gene, ranging from one base pair to 11–31 kb in size. It has been identified in two types of
mental retardation and/or decreased fertility [Heller et al. 2015; Morice-Picard et al. 2009].
Novel Contiguous Gen Deletion TTD4 & GA3 7
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Phenotypically, non-cutaneous common aspects in TTD4 consist in: microcephaly,
intellectual disability, growth failure, axial osteosclerosis, osteopenia and decreased fertility.
The cutaneous features affect mainly nails and hair, the latter consists in short, woolly,
sparse, brittle hair, trichorrhexis, reduced cystine or sulfur content of hair [Cheng & Bayliss
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In Table I we summarize the clinical and molecular findings in our patient compared
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to other reported patients with TTD4 and mutations in MPLKIP gene, some of them had
consanguineous parents. Despite the wide clinical variability; all cases described had
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dysmorphic facies, psychomotor delay; brittle and sparse eyebrows, eyelashes, and hair
trichorrhexis nodosa with abnormal light microscopy appearance. The molecular findings
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showed different kinds of mutations in one or both alleles of MPLKIP, from point mutations
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to CNVs, causing dysfunctional or absent protein.
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Glutaric Aciduria type 3 (GA3, MIM 231690; GARD 12469; ORPHA 35706) is a
acid without specific phenotype, although some individuals remain asymptomatic [Bennett,
Bennett et al. described the first case reported of a patient with glutaric aciduria, a 1-
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urinary amounts of glutaric acid and lack of detectable activity of peroxisomal glutaryl-CoA
oxidase [Bennett et al. 1991]. Knerr et al. reported 3 cases with no distinctive phenotype
[Knerr et al., 2002], Sherman et al. also reported 3 healthy children who excreted large
quantities of glutarate but low 3-hydroxyglutarate, consistent with the phenotype of glutaric
aciduria III after the screening of 1,223 Amish infants. They did not receive treatment and
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ACKNOWLEDGMENTS
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The authors wish to thank the family for their participation in this study. We would
also like to thank Genetic and Inborn Errors of Metabolism Team of ´Instituto Nacional de
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Salud del Niño´ for their contribution, assistance and suggestions. The authors have no
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Novel Contiguous Gen Deletion TTD4 & GA3 9
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REFERENCES
Bennett, M. J., Pollitt, R. J., Goodman, S. I., Hale, D. E., & Vamecq, J. (1991). Atypical
14(2), 165–173.
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Bergmann, E., & Egly, J.M. (2017). Trichothiodystrophy, a transcription syndrome: Trends
RI
in Genetics. TRENDS in Genetics, 17 (5), 279-286.
Cheng, A. S., & Bayliss, S. J. (2008). The genetics of hair shaft disorders. Journal of the
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American Academy of Dermatology, 59(1), 1-22; 23-26.
Faghri, S., Tamura, D., Kraemer, K. H., & DiGiovanna, J. J. (2008). Trichothiodystrophy: a
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systematic review of 112 published cases characterises a wide spectrum of clinical
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manifestations. Journal of medical genetics, 45(10), 609-621.
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Gummer, C. l., & Dawber, R. (1985). Trichothiodystrophy: an ultrastructural study of the hair
Hashimoto, S., & Egly, J. M. (2009). Trichothiodystrophy view from the molecular basis of
TE
230.
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Heller, E. R., Khan, S. G., Kuschal, C., Tamura, D., DiGiovanna, J. J., & Kraemer, K. H.
C
734-741.
Knerr, I., Zschocke, J., Trautmann, U., Dorland, L., de Koning, T. J., Müller, P., …
Morice-Picard, F., Cario-André, M., Rezvani, H., Lacombe, D., Sarasin, A., & Taïeb, A.
PT
(2009). New clinico-genetic classification of trichothiodystrophy. American Journal
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of Medical Genetics Part A, 149A(9), 2020-2030.
Pode-Shakked, B., Marek-Yagel, D., Greenberger, S., Pode-Shakked, N., Pras, E., Barzilai,
SC
A., … Anikster, Y. (2015). A novel mutation in the C7orf11 gene causes
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European Journal of Medical Genetics, 58(12), 685–688.
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Sherman, E. A., Strauss, K. A., Tortorelli, S., Bennett, M. J., Knerr, I., Morton, D. H., &
M
Stefanini, M., Botta, E., Lanzafame, M., & Orioli, D. (2010). Trichothiodystrophy: from
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Verma, R., Babu, A. (1995). Human Chromosomes: Principles & Techniques, 2nd edition,
Waters, P. J., Kitzler, T. M., Feigenbaum, A., Geraghty, M. T., Al-Dirbashi, O., Bherer, P.,
Berlin, Heidelberg.
Novel Contiguous Gen Deletion TTD4 & GA3 11
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La Serna-Infantes et al. 12
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Table I: Comparative clinical/molecular features described in patients with TTD4.
(b), (c) Frontal and (d) lateral view clinical features. Microcephaly;
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prematurely aged face, asymmetric face with hypoplasic superciliary and
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zygomatic arches; dark, short, sparse, coarse and brittle scalp hair, eyebrows
and eyelashes; widespread alopecic parietal area; mild anteverted ears with
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prominent antihelix and hypoplasic lobes; thick nasal root and anteverted nares
with skin excoriation, downslanting mouth corners. Some small ´café au lait´
patches.
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(e) Follicular keratosis on the back, ´café au lait´ patch.
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(f) Short, thin and irregular nails of the fingers; brachydactyly, bilateral
Nakabayashi et
Przedborski et
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CLINICAL AND MOLECULAR CHARACTERISTICS Botta et al. , 2007 Heller et al ., 2015
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Country / City / Ethnicity Italy Italy India Iraq Neth Morocco / Canad Italy Caucasian Peru
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Sex F F F F M F M F F n F M F F M M F
Age (years) 8 4 3 6 3 3 16 4 13 n 3 14 4 2 1 14 8
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Consanguineous Parents - n N n n n + + + n - - - - - - -
Short stature + n N n n n + + - n - - - - - + +
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Microcephaly + n N n n n + + + n + - - - - - +
Cortical atrophy (rare) n n N n n n + - + n + - - - - - -
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Dysmorphic features + n N n n n + + + n + + + + + + +
Hypotonia n N n n n + + + n + + + + + + -
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Nystagmus n n N n n n n n n n + + - - - - +
Ataxia n n n n n n + + + n n - - - - - -
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Psychomotor delay + n n n n n + + + + + + + + + + +
Dysmorphic/dyschromic nails + n n n n n - - - + + - - + + + +
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Brittle, sparse eyebrows/eyelashes/hair + n n n n n + + + + + + + + + + +
Trichorrhexis nodosa + n n n n n + + + n + + + + + n +
Alopecia Areata + n n n n n + + + n + n n n n n +
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Mutation in MPLKIP
(+): Present at the study (-): Absent at study (n): Not described. (p): Paternal allele. (m): Maternal allele
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p m p m p m p m p m p m
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No protein Deletion of11-31kb
n
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+
p.His50AlafsX8 c.148_152delCACAC
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n
n
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p.Ser93ProfsX60 c.277delT
n
n
n
n
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p.His50AlafsX8 c.148_152delCACAC
p.Arg77GlyfsX76 c.229delC
n
n
n
n
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n
n
n
n
p.Ser93ProfsX60 c.277delT
n
n
n
n
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n
n
n
+
p
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57 residue
c.187_188delCG
n
n
n
+
truncated protein
m
n
n
n
+
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p m p m
p.Met144Val c.480A>G
n
n
n
n
+
+
+
-
m
p.Gly76Alafs*77 c.227delG
p
+
+
+
-
m
+
+
-
m
p.Ser93Profs*60 c. 277delT
+
+
+
-
p m p m
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