- Email: [email protected]
Novel truncating PPM1D mutation in a patient with intellectual disability
Accepted Manuscript Novel truncating PPM1D mutation in a patient with intellectual disability Joseph Porrmann, Andreas Rump, Karl Hackmann, Nataliya Di Donato, Anne-Karin Kahlert, Johannes Wagner, Arne Jahn, Ines Eger, Monika Flury, Evelin Schrock, Andreas Tzschach, Laura Gieldon PII:
S1769-7212(18)30067-3
DOI:
10.1016/j.ejmg.2018.05.006
Reference:
EJMG 3464
To appear in:
European Journal of Medical Genetics
Received Date: 25 January 2018 Revised Date:
24 March 2018
Accepted Date: 8 May 2018
Please cite this article as: J. Porrmann, A. Rump, K. Hackmann, N. Di Donato, A.-K. Kahlert, J. Wagner, A. Jahn, I. Eger, M. Flury, E. Schrock, A. Tzschach, L. Gieldon, Novel truncating PPM1D mutation in a patient with intellectual disability, European Journal of Medical Genetics (2018), doi: 10.1016/ j.ejmg.2018.05.006. This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.
1
ACCEPTED MANUSCRIPT Novel truncating PPM1D mutation in a patient with intellectual disability Joseph Porrmanna, Andreas Rumpa, Karl Hackmanna, Nataliya Di Donatoa, AnneKarin Kahlerta, Johannes Wagnera, Arne Jahna, Ines Egerb, Monika Fluryc, Evelin Schrocka, Andreas Tzschacha, Laura Gieldona
RI PT
a Institut für Klinische Genetik, Medizinische Fakultät Carl Gustav Carus, Technische Universität Dresden, Fetscherstraße 74, 01307 Dresden, Germany b Sozialpädiatrisches Zentrum, Städtisches Klinikum Görlitz gGmbH, Girbigsdorfer Straße 1 - 3, 02828 Görlitz, Germany
Laura Gieldon
EP
Corresponding author:
TE D
M AN U
Running head: PPM1D mutations in ID
SC
c Endokrinologische Ambulanz, Klinik und Poliklinik für Kinder- und Jugendmedizin, Universitätsklinikum Carl Gustav Carus Dresden, Fetscherstraße 74, 01307 Dresden, Germany
AC C
Institut für Klinische Genetik
Medizinische Fakultät Carl Gustav Carus Technische Universität Dresden Fetscherstraße 74 01307 Dresden Germany Email: [email protected] Tel.:
+49 (351) 458 4278
Fax:
+49 (351) 458 4316
2
ACCEPTED MANUSCRIPT Abstract Truncating mutations in the last and penultimate exons of the PPM1D gene were recently described as a cause for mild to severe intellectual disability in fourteen patients. Feeding difficulties, periods of fever and vomiting as well as a high pain
RI PT
threshold were described as additional characteristic features and the disorder was subsequently termed “intellectual developmental disorder with gastrointestinal
difficulties and high pain threshold (IDDGIP)” in the OMIM database (MIM # 617450).
SC
Here we report on an additional patient carrying a novel de novo truncating mutation NM_003620.3: c.1535del, p.(Asn512Ilefs*2) in the last exon of PPM1D. While the
M AN U
patient showed features overlapping with the reported phenotype, such as a short stature and small hands and feet, he also presented with additional features like cleft lip and palate and an aberrant right subclavian artery. Notably, the patient did not have any gastrointestinal difficulties or periods of fever, indicating variability of the
Keywords
TE D
phenotype of patients with PPM1D mutations.
AC C
EP
PPM1D; high pain threshold; intellectual disability; short stature; cleft lip and palate
3
ACCEPTED MANUSCRIPT Introduction
PPM1D (protein phosphatase, Mg2+/Mn2+-dependent 1D [MIM: 605100]) encodes for a phosphatase that was initally described within the context of tumorigenesis and DNA damage response. By dephosphorylation and inactivation of multiple tumor
RI PT
suppressors, including p53, PPM1D forms negative feedback loops to inhibit
apoptosis and cell cycle arrest (Lu et al., 2008). Recently, Jansen and coworkers identified truncating mutations in the last and penultimate exons of PPM1D to cause
SC
a syndrome which is characterized by intellectual disability, behavioral problems, hypotonia, broad-based gait, periods of fever and vomiting, high pain threshold, short
M AN U
stature, small hands and feet and facial dysmorphisms (Jansen et al., 2017; Lelieveld et al., 2016; McRae, 2017; Sanders et al., 2012).
The authors suggested that the mechanism underlying pathogenicity is an escape from nonsense-mediated mRNA decay that is restricted to truncating mutations
TE D
occurring in the last and penultimate exons of PPM1D (Jansen, et al., 2017). A similar mechanism has been proposed to underly other syndromes as well, such as Floating-Harbor syndrome, Robinow syndrome and Hajdu-Cheney syndrome (Isidor
EP
et al., 2011; Seifert et al., 2014; J. White et al., 2015; J. J. White et al., 2016). The
AC C
authors suggested that the mutated PPM1D protein might subsequently reduce cell proliferation that in turn results in IDDGIP (Jansen, et al., 2017). Here we report on a 6 year-old boy with a novel mutation in PPM1D who presented with additional clinical features including cleft lip and palate, an aberrant right subclavian artery and a single transverse palmar crease of the left hand which has hitherto not been reported in patients with this disorder.
4
ACCEPTED MANUSCRIPT Clinical report Prenatal ultrasound examinations of the male patient revealed a unilateral cleft lip and palate, an aberrant right subclavian artery, increased nuchal translucency and intrauterine growth at the lower limit of the normal range. He was born in the 38+2
RI PT
gestational week by spontaneous delivery. The patient was hypotrophic at birth with a weight of 2230 g (
occipitofrontal circumference (OFC) of 32.5 cm (P3; -1.84 z). Postnatally, he
SC
developed recurrent apnea, which ceased under caffeine therapy. Additionally, a unilateral intracerebral hemorrhage I° was diagnosed by ultrasound. A mild
M AN U
combined developmental disorder was determined. The patient was able to walk at 2 years of age and started to speak first words at 18 months. At the last examination at 6 3/12 years the patient attended a kindergarten with a special education track. Speech development had considerably progressed (full sentences), while a mild
TE D
global developmental delay persisted and school enrollment was planned a year later than usual at 7 years of age. Whether regular schooling could be an option remained uncertain at the time of the last examination. Short stature had persisted
EP
[length 105.7 cm (
AC C
The parents described a short attention span in their son but no other behavioral features. Facial features included a broad forehead, arched eyebrows, strabismus, low-set posteriorly rotated ears and a wide mouth with a scar resulting from surgical treatment of the cleft lip and cleft palate (Fig. 1 A - D). The hands and feet were small and a single crease of the left hand was observed (Fig 1 E - G). Besides convergent strabismus, an ophthalmological examination revealed astigmatism and myopia. An X-ray examination of the left hand showed delayed bone age and further identified brachyphalangia with an emphasis on the metaphalanges of digits II to V.
5
ACCEPTED MANUSCRIPT
Aditionally, a hyperlordosis could be observed (Fig 1 B). When questioned, the father confirmed he had observed an unusually high pain threshold in the patient. A brain MRI has never been performed. Conventional chromosome analysis and array CGH were normal. The patient’s parents were healthy and non-consanguineous. There
RI PT
was no history of cleft lip and/or cleft palate in the family. Supplementary Table 1 adds the clinical features of the current patient to the table presented by Jansen et
SC
al. for the purpose of comparison.
By trio sequencing of the coding exons of 4,813 genes that are associated with
M AN U
known clinical phenotypes (TruSight-One kit, Illumina, San Diego, CA), we identified a heterozygous de novo mutation in PPM1D: NM_003620.3: c.1535del, p.(Asn512Ilefs*2) in the patient (Supplementary Figure 1 (A)). The mutation was confirmed in the patient and excluded in the parents by Sanger sequencing. No other
Discussion
TE D
variants with pathogenic potential were detected.
EP
In fourteen unrelated patients, truncating mutations in the last and penultimate exons
AC C
of the PPM1D gene were identified as a cause for mild to severe intellectual disability by Jansen and coworkers (2017). Further symptoms were described in these patients, including a high pain threshold in 90% of cases. Moreover, feeding difficulties (71%) and periods of illness with fever and/or vomiting (62%) were listed as common features (Jansen, et al., 2017). Because of these anomalies, the disease has been termed “intellectual developmental disorder with gastrointestinal difficulties and high pain threshold (IDDGIP)” in the OMIM database (MIM # 617450). Here we report on a further patient with a novel truncating mutation in the last exon of
6
ACCEPTED MANUSCRIPT
PPM1D. The mutation c.1535del, p.(Asn512Ilefs*2) is located in exon 6 and situated between two mutations that have prior been reported as pathogenic by Jansen et al. (Supplementary Figure 1 (B)). Notably, our patient had no feeding difficulties or periods of illness and consequently the term IDDGIP did not fully apply to him. This
RI PT
indicates variability in the phenotype of patients with PPM1D mutations. In
accordance with the study of Jansen and coworkers, our patient revealed a high pain threshold, vision problems and small hands. Brachyphalangia was formerly noticed
SC
in over 90% of the patients with PPM1D mutations and seems to be one of the main physical characteristics. The patient also showed facial features overlapping with
M AN U
earlier cases, including a broad forehead, low-set posteriorly rotated ears and a wide mouth. As observed in eight of the originally described individuals, our patient also had a short stature, suggesting PPM1D might be relevant for normal growth. Moreover, he presented additional clinical features like cleft lip and palate, an
TE D
aberrant right subclavian artery and single crease of the left hand. While these rather frequent features might have developed independent from the mutation, it seems reasonable to assume they might be part of the clinical spectrum of PPM1D
EP
mutations. Reports of additional patients will be needed for a comprehensive
AC C
delineation of the clinical spectrum of this novel disorder.
Acknowledgements
We would like to thank the patient and his parents for participating in this work.
Declaration of interests and funding We declare no conflicts of interest.This research did not receive any specific grant from funding agencies in the public, commercial, or not-for-profit sectors.
7
ACCEPTED MANUSCRIPT
Figure ledgends Fig. 1: (A-D) The proband at 6 3/12 years of age. Note hyperlordosis, broad forehead, arched eyebrows, strabismus, low-set posteriorly rotated ears and a wide
RI PT
mouth with a scar resulting from surgical treatment of the cleft lip and palate as well as small hands and feet.
SC
Supplementary data
Supplementary Figure 1: Depiction of the PPM1D mutation identified in the
M AN U
index patient. (A) Next generation sequencing reads as depicted by the CLC Biomedical Genomics Workbench showing the mutation c.1535delA in the index patient (lower graph).The mutation was excluded in both parents (upper und middle graphs). (B) Representation of mutations in exons 5 and 6 of the PPM1D gene
TE D
identified by Jansen et al. (black stripes) and in our patient (red stripe/ arrow) as depicted using the UCSC genome bowser at http://genome.ucsc.edu/ (Casper et al., 2017; Jansen, et al., 2017).
EP
Supplementary Table 1: Comparison of clinical features observed in the inital
AC C
cohort described by Jansen et al. (2017) and in the patient presented in this report. This table was copied from Jansen et al. (2017) and editied for the purpose of comparison.
8
ACCEPTED MANUSCRIPT References
Casper, J., Zweig, A. S., Villarreal, C., Tyner, C., Speir, M. L., Rosenbloom, K. R., . . . Kent, W. J. (2017). The UCSC Genome Browser database: 2018 update. Nucleic Acids Res. doi: 10.1093/nar/gkx1020
RI PT
Isidor, B., Lindenbaum, P., Pichon, O., Bezieau, S., Dina, C., Jacquemont, S., . . . Le Caignec, C. (2011). Truncating mutations in the last exon of NOTCH2 cause a rare skeletal disorder with osteoporosis. Nat Genet, 43(4), 306-308. doi:
SC
10.1038/ng.778
Jansen, S., Geuer, S., Pfundt, R., Brough, R., Ghongane, P., Herkert, J. C., . . . de
M AN U
Vries, B. B. (2017). De Novo Truncating Mutations in the Last and Penultimate Exons of PPM1D Cause an Intellectual Disability Syndrome. Am J Hum Genet, 100(4), 650-658. doi: 10.1016/j.ajhg.2017.02.005 Lelieveld, S. H., Reijnders, M. R., Pfundt, R., Yntema, H. G., Kamsteeg, E. J., de
TE D
Vries, P., . . . Gilissen, C. (2016). Meta-analysis of 2,104 trios provides support for 10 new genes for intellectual disability. Nat Neurosci, 19(9), 11941196. doi: 10.1038/nn.4352
EP
Lu, X., Nguyen, T. A., Moon, S. H., Darlington, Y., Sommer, M., & Donehower, L. A. (2008). The type 2C phosphatase Wip1: an oncogenic regulator of tumor
AC C
suppressor and DNA damage response pathways. Cancer Metastasis Rev, 27(2), 123-135. doi: 10.1007/s10555-008-9127-x
McRae. (2017). Prevalence and architecture of de novo mutations in developmental disorders. Nature, 542(7642), 433-438. doi: 10.1038/nature21062 Sanders, S. J., Murtha, M. T., Gupta, A. R., Murdoch, J. D., Raubeson, M. J., Willsey, A. J., . . . State, M. W. (2012). De novo mutations revealed by whole-
9
ACCEPTED MANUSCRIPT exome sequencing are strongly associated with autism. Nature, 485(7397), 237-241. doi: 10.1038/nature10945 Seifert, W., Meinecke, P., Kruger, G., Rossier, E., Heinritz, W., Wusthof, A., & Horn, D. (2014). Expanded spectrum of exon 33 and 34 mutations in SRCAP and
127. doi: 10.1186/s12881-014-0127-0
RI PT
follow-up in patients with Floating-Harbor syndrome. BMC Med Genet, 15,
White, J., Mazzeu, J. F., Hoischen, A., Jhangiani, S. N., Gambin, T., Alcino, M. C., . .
SC
. Carvalho, C. M. (2015). DVL1 frameshift mutations clustering in the
penultimate exon cause autosomal-dominant Robinow syndrome. Am J Hum
M AN U
Genet, 96(4), 612-622. doi: 10.1016/j.ajhg.2015.02.015
White, J. J., Mazzeu, J. F., Hoischen, A., Bayram, Y., Withers, M., Gezdirici, A., . . . Carvalho, C. M. B. (2016). DVL3 Alleles Resulting in a -1 Frameshift of the Last Exon Mediate Autosomal-Dominant Robinow Syndrome. Am J Hum
AC C
EP
TE D
Genet, 98(3), 553-561. doi: 10.1016/j.ajhg.2016.01.005
AC C
EP
TE D
M AN U
SC
RI PT
ACCEPTED MANUSCRIPT
S1769-7212(18)30067-3
DOI:
10.1016/j.ejmg.2018.05.006
Reference:
EJMG 3464
To appear in:
European Journal of Medical Genetics
Received Date: 25 January 2018 Revised Date:
24 March 2018
Accepted Date: 8 May 2018
Please cite this article as: J. Porrmann, A. Rump, K. Hackmann, N. Di Donato, A.-K. Kahlert, J. Wagner, A. Jahn, I. Eger, M. Flury, E. Schrock, A. Tzschach, L. Gieldon, Novel truncating PPM1D mutation in a patient with intellectual disability, European Journal of Medical Genetics (2018), doi: 10.1016/ j.ejmg.2018.05.006. This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.
1
ACCEPTED MANUSCRIPT Novel truncating PPM1D mutation in a patient with intellectual disability Joseph Porrmanna, Andreas Rumpa, Karl Hackmanna, Nataliya Di Donatoa, AnneKarin Kahlerta, Johannes Wagnera, Arne Jahna, Ines Egerb, Monika Fluryc, Evelin Schrocka, Andreas Tzschacha, Laura Gieldona
RI PT
a Institut für Klinische Genetik, Medizinische Fakultät Carl Gustav Carus, Technische Universität Dresden, Fetscherstraße 74, 01307 Dresden, Germany b Sozialpädiatrisches Zentrum, Städtisches Klinikum Görlitz gGmbH, Girbigsdorfer Straße 1 - 3, 02828 Görlitz, Germany
Laura Gieldon
EP
Corresponding author:
TE D
M AN U
Running head: PPM1D mutations in ID
SC
c Endokrinologische Ambulanz, Klinik und Poliklinik für Kinder- und Jugendmedizin, Universitätsklinikum Carl Gustav Carus Dresden, Fetscherstraße 74, 01307 Dresden, Germany
AC C
Institut für Klinische Genetik
Medizinische Fakultät Carl Gustav Carus Technische Universität Dresden Fetscherstraße 74 01307 Dresden Germany Email: [email protected] Tel.:
+49 (351) 458 4278
Fax:
+49 (351) 458 4316
2
ACCEPTED MANUSCRIPT Abstract Truncating mutations in the last and penultimate exons of the PPM1D gene were recently described as a cause for mild to severe intellectual disability in fourteen patients. Feeding difficulties, periods of fever and vomiting as well as a high pain
RI PT
threshold were described as additional characteristic features and the disorder was subsequently termed “intellectual developmental disorder with gastrointestinal
difficulties and high pain threshold (IDDGIP)” in the OMIM database (MIM # 617450).
SC
Here we report on an additional patient carrying a novel de novo truncating mutation NM_003620.3: c.1535del, p.(Asn512Ilefs*2) in the last exon of PPM1D. While the
M AN U
patient showed features overlapping with the reported phenotype, such as a short stature and small hands and feet, he also presented with additional features like cleft lip and palate and an aberrant right subclavian artery. Notably, the patient did not have any gastrointestinal difficulties or periods of fever, indicating variability of the
Keywords
TE D
phenotype of patients with PPM1D mutations.
AC C
EP
PPM1D; high pain threshold; intellectual disability; short stature; cleft lip and palate
3
ACCEPTED MANUSCRIPT Introduction
PPM1D (protein phosphatase, Mg2+/Mn2+-dependent 1D [MIM: 605100]) encodes for a phosphatase that was initally described within the context of tumorigenesis and DNA damage response. By dephosphorylation and inactivation of multiple tumor
RI PT
suppressors, including p53, PPM1D forms negative feedback loops to inhibit
apoptosis and cell cycle arrest (Lu et al., 2008). Recently, Jansen and coworkers identified truncating mutations in the last and penultimate exons of PPM1D to cause
SC
a syndrome which is characterized by intellectual disability, behavioral problems, hypotonia, broad-based gait, periods of fever and vomiting, high pain threshold, short
M AN U
stature, small hands and feet and facial dysmorphisms (Jansen et al., 2017; Lelieveld et al., 2016; McRae, 2017; Sanders et al., 2012).
The authors suggested that the mechanism underlying pathogenicity is an escape from nonsense-mediated mRNA decay that is restricted to truncating mutations
TE D
occurring in the last and penultimate exons of PPM1D (Jansen, et al., 2017). A similar mechanism has been proposed to underly other syndromes as well, such as Floating-Harbor syndrome, Robinow syndrome and Hajdu-Cheney syndrome (Isidor
EP
et al., 2011; Seifert et al., 2014; J. White et al., 2015; J. J. White et al., 2016). The
AC C
authors suggested that the mutated PPM1D protein might subsequently reduce cell proliferation that in turn results in IDDGIP (Jansen, et al., 2017). Here we report on a 6 year-old boy with a novel mutation in PPM1D who presented with additional clinical features including cleft lip and palate, an aberrant right subclavian artery and a single transverse palmar crease of the left hand which has hitherto not been reported in patients with this disorder.
4
ACCEPTED MANUSCRIPT Clinical report Prenatal ultrasound examinations of the male patient revealed a unilateral cleft lip and palate, an aberrant right subclavian artery, increased nuchal translucency and intrauterine growth at the lower limit of the normal range. He was born in the 38+2
RI PT
gestational week by spontaneous delivery. The patient was hypotrophic at birth with a weight of 2230 g (
occipitofrontal circumference (OFC) of 32.5 cm (P3; -1.84 z). Postnatally, he
SC
developed recurrent apnea, which ceased under caffeine therapy. Additionally, a unilateral intracerebral hemorrhage I° was diagnosed by ultrasound. A mild
M AN U
combined developmental disorder was determined. The patient was able to walk at 2 years of age and started to speak first words at 18 months. At the last examination at 6 3/12 years the patient attended a kindergarten with a special education track. Speech development had considerably progressed (full sentences), while a mild
TE D
global developmental delay persisted and school enrollment was planned a year later than usual at 7 years of age. Whether regular schooling could be an option remained uncertain at the time of the last examination. Short stature had persisted
EP
[length 105.7 cm (
AC C
The parents described a short attention span in their son but no other behavioral features. Facial features included a broad forehead, arched eyebrows, strabismus, low-set posteriorly rotated ears and a wide mouth with a scar resulting from surgical treatment of the cleft lip and cleft palate (Fig. 1 A - D). The hands and feet were small and a single crease of the left hand was observed (Fig 1 E - G). Besides convergent strabismus, an ophthalmological examination revealed astigmatism and myopia. An X-ray examination of the left hand showed delayed bone age and further identified brachyphalangia with an emphasis on the metaphalanges of digits II to V.
5
ACCEPTED MANUSCRIPT
Aditionally, a hyperlordosis could be observed (Fig 1 B). When questioned, the father confirmed he had observed an unusually high pain threshold in the patient. A brain MRI has never been performed. Conventional chromosome analysis and array CGH were normal. The patient’s parents were healthy and non-consanguineous. There
RI PT
was no history of cleft lip and/or cleft palate in the family. Supplementary Table 1 adds the clinical features of the current patient to the table presented by Jansen et
SC
al. for the purpose of comparison.
By trio sequencing of the coding exons of 4,813 genes that are associated with
M AN U
known clinical phenotypes (TruSight-One kit, Illumina, San Diego, CA), we identified a heterozygous de novo mutation in PPM1D: NM_003620.3: c.1535del, p.(Asn512Ilefs*2) in the patient (Supplementary Figure 1 (A)). The mutation was confirmed in the patient and excluded in the parents by Sanger sequencing. No other
Discussion
TE D
variants with pathogenic potential were detected.
EP
In fourteen unrelated patients, truncating mutations in the last and penultimate exons
AC C
of the PPM1D gene were identified as a cause for mild to severe intellectual disability by Jansen and coworkers (2017). Further symptoms were described in these patients, including a high pain threshold in 90% of cases. Moreover, feeding difficulties (71%) and periods of illness with fever and/or vomiting (62%) were listed as common features (Jansen, et al., 2017). Because of these anomalies, the disease has been termed “intellectual developmental disorder with gastrointestinal difficulties and high pain threshold (IDDGIP)” in the OMIM database (MIM # 617450). Here we report on a further patient with a novel truncating mutation in the last exon of
6
ACCEPTED MANUSCRIPT
PPM1D. The mutation c.1535del, p.(Asn512Ilefs*2) is located in exon 6 and situated between two mutations that have prior been reported as pathogenic by Jansen et al. (Supplementary Figure 1 (B)). Notably, our patient had no feeding difficulties or periods of illness and consequently the term IDDGIP did not fully apply to him. This
RI PT
indicates variability in the phenotype of patients with PPM1D mutations. In
accordance with the study of Jansen and coworkers, our patient revealed a high pain threshold, vision problems and small hands. Brachyphalangia was formerly noticed
SC
in over 90% of the patients with PPM1D mutations and seems to be one of the main physical characteristics. The patient also showed facial features overlapping with
M AN U
earlier cases, including a broad forehead, low-set posteriorly rotated ears and a wide mouth. As observed in eight of the originally described individuals, our patient also had a short stature, suggesting PPM1D might be relevant for normal growth. Moreover, he presented additional clinical features like cleft lip and palate, an
TE D
aberrant right subclavian artery and single crease of the left hand. While these rather frequent features might have developed independent from the mutation, it seems reasonable to assume they might be part of the clinical spectrum of PPM1D
EP
mutations. Reports of additional patients will be needed for a comprehensive
AC C
delineation of the clinical spectrum of this novel disorder.
Acknowledgements
We would like to thank the patient and his parents for participating in this work.
Declaration of interests and funding We declare no conflicts of interest.This research did not receive any specific grant from funding agencies in the public, commercial, or not-for-profit sectors.
7
ACCEPTED MANUSCRIPT
Figure ledgends Fig. 1: (A-D) The proband at 6 3/12 years of age. Note hyperlordosis, broad forehead, arched eyebrows, strabismus, low-set posteriorly rotated ears and a wide
RI PT
mouth with a scar resulting from surgical treatment of the cleft lip and palate as well as small hands and feet.
SC
Supplementary data
Supplementary Figure 1: Depiction of the PPM1D mutation identified in the
M AN U
index patient. (A) Next generation sequencing reads as depicted by the CLC Biomedical Genomics Workbench showing the mutation c.1535delA in the index patient (lower graph).The mutation was excluded in both parents (upper und middle graphs). (B) Representation of mutations in exons 5 and 6 of the PPM1D gene
TE D
identified by Jansen et al. (black stripes) and in our patient (red stripe/ arrow) as depicted using the UCSC genome bowser at http://genome.ucsc.edu/ (Casper et al., 2017; Jansen, et al., 2017).
EP
Supplementary Table 1: Comparison of clinical features observed in the inital
AC C
cohort described by Jansen et al. (2017) and in the patient presented in this report. This table was copied from Jansen et al. (2017) and editied for the purpose of comparison.
8
ACCEPTED MANUSCRIPT References
Casper, J., Zweig, A. S., Villarreal, C., Tyner, C., Speir, M. L., Rosenbloom, K. R., . . . Kent, W. J. (2017). The UCSC Genome Browser database: 2018 update. Nucleic Acids Res. doi: 10.1093/nar/gkx1020
RI PT
Isidor, B., Lindenbaum, P., Pichon, O., Bezieau, S., Dina, C., Jacquemont, S., . . . Le Caignec, C. (2011). Truncating mutations in the last exon of NOTCH2 cause a rare skeletal disorder with osteoporosis. Nat Genet, 43(4), 306-308. doi:
SC
10.1038/ng.778
Jansen, S., Geuer, S., Pfundt, R., Brough, R., Ghongane, P., Herkert, J. C., . . . de
M AN U
Vries, B. B. (2017). De Novo Truncating Mutations in the Last and Penultimate Exons of PPM1D Cause an Intellectual Disability Syndrome. Am J Hum Genet, 100(4), 650-658. doi: 10.1016/j.ajhg.2017.02.005 Lelieveld, S. H., Reijnders, M. R., Pfundt, R., Yntema, H. G., Kamsteeg, E. J., de
TE D
Vries, P., . . . Gilissen, C. (2016). Meta-analysis of 2,104 trios provides support for 10 new genes for intellectual disability. Nat Neurosci, 19(9), 11941196. doi: 10.1038/nn.4352
EP
Lu, X., Nguyen, T. A., Moon, S. H., Darlington, Y., Sommer, M., & Donehower, L. A. (2008). The type 2C phosphatase Wip1: an oncogenic regulator of tumor
AC C
suppressor and DNA damage response pathways. Cancer Metastasis Rev, 27(2), 123-135. doi: 10.1007/s10555-008-9127-x
McRae. (2017). Prevalence and architecture of de novo mutations in developmental disorders. Nature, 542(7642), 433-438. doi: 10.1038/nature21062 Sanders, S. J., Murtha, M. T., Gupta, A. R., Murdoch, J. D., Raubeson, M. J., Willsey, A. J., . . . State, M. W. (2012). De novo mutations revealed by whole-
9
ACCEPTED MANUSCRIPT exome sequencing are strongly associated with autism. Nature, 485(7397), 237-241. doi: 10.1038/nature10945 Seifert, W., Meinecke, P., Kruger, G., Rossier, E., Heinritz, W., Wusthof, A., & Horn, D. (2014). Expanded spectrum of exon 33 and 34 mutations in SRCAP and
127. doi: 10.1186/s12881-014-0127-0
RI PT
follow-up in patients with Floating-Harbor syndrome. BMC Med Genet, 15,
White, J., Mazzeu, J. F., Hoischen, A., Jhangiani, S. N., Gambin, T., Alcino, M. C., . .
SC
. Carvalho, C. M. (2015). DVL1 frameshift mutations clustering in the
penultimate exon cause autosomal-dominant Robinow syndrome. Am J Hum
M AN U
Genet, 96(4), 612-622. doi: 10.1016/j.ajhg.2015.02.015
White, J. J., Mazzeu, J. F., Hoischen, A., Bayram, Y., Withers, M., Gezdirici, A., . . . Carvalho, C. M. B. (2016). DVL3 Alleles Resulting in a -1 Frameshift of the Last Exon Mediate Autosomal-Dominant Robinow Syndrome. Am J Hum
AC C
EP
TE D
Genet, 98(3), 553-561. doi: 10.1016/j.ajhg.2016.01.005
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