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A new familial case of microdeletion syndrome 10p15.3
European Journal of Medical Genetics 59 (2016) 179e182
Contents lists available at ScienceDirect
European Journal of Medical Genetics journal homepage: http://www.elsevier.com/locate/ejmg
A new familial case of microdeletion syndrome 10p15.3 Marlene Eggert a, *, Stefan Müller a, Uwe Heinrich b, Yasmin Mehraein a a b
Institute of Human Genetics, University Hospital, LMU Munich, Munich, Germany Center for Human Genetics and Laboratory Medicine, Dres. Klein and Rost, Martinsried, Germany
a r t i c l e i n f o
a b s t r a c t
Article history: Received 23 December 2015 Received in revised form 9 February 2016 Accepted 21 February 2016 Available online 24 February 2016
In 2012 a small terminal deletion in the short arm of chromosome 10 in the region 10p15.3 was reported as a novel microdeletion syndrome. By now 21 patients, including a single familial case, have been reported. Characteristic findings comprise variable cognitive impairment or developmental delay, disorder of speech development, as well as various dysmorphic signs. We here report on a new patient, an eight year old girl, with a microdeletion syndrome 10p15.3. She is a foster child showing intellectual deficits, disorder of speech development, behavioral problems, congenital heart defect, and several dysmorphic signs. The same microdeletion was subsequently found in the six year old maternal half-sister, showing very similar developmental and cognitive issues, including major speech impairment. The mother has not obtained a school degree. She was described as being a dissocial person with severe alcohol abuse and showing minor cognitive disability. Thus inheritance of the microdeletion from a probably symptomatic mother can be assumed. The patients presented here add up to the as yet small number of reported cases of microdeletion 10p15.3 and thereby might help to establish a more comprehensive clinical spectrum of this rather newly discovered syndrome. © 2016 Elsevier Masson SAS. All rights reserved.
Keywords: Microdeletion 10p15.3 syndrome Language disorder
1. Introduction Besides monogenic defects and classical chromosomal aberrations submicroscopic chromosomal imbalances comprising microdeletions and microduplications account for a major group of clinically important genetic alterations. A number of previously well-defined genetic syndromes were identified as microdeletion or microduplication syndromes. The diagnostic use of array-CGH to address clinically unclear or nonspecific conditions, in particular syndromic intellectual disability, allows the identification of novel recurrent micro-imbalances representing new microdeletion/ microduplication syndromes (Carvill and Mefford, 2013; Vissers et al., 2010). Quite recently a small subgroup of patients with similar microdeletions in the short arm of chromosome 10 was defined as a new microdeletion syndrome 10p15.3. To date only 23 patients, and among them only one familial case, showing variable chromosomal breakpoints and deletion sizes, have been reported. Clinical data was available from only 15 of the 21 published patients (DeScipio et al., 2012; Vargiami et al., 2014). Characteristic clinical
* Corresponding author. Institute of Human Genetics, University Hospital of Ludwig-Maximilians-University Munich, Goethestr. 29, D-80336, Munich, Germany. E-mail address: [email protected] (M. Eggert). http://dx.doi.org/10.1016/j.ejmg.2016.02.008 1769-7212/© 2016 Elsevier Masson SAS. All rights reserved.
findings in affected individuals described so far comprised variable cognitive impairment or developmental delay, speech delay and disorder of speech development, as well as uncharacterized dysmorphic signs (DeScipio et al., 2012; Vargiami et al., 2014). However, this rather nonspecific phenotype still needs to be refined by adding detailed information from further patients. We here report on a new familial case of microdeletion syndrome 10p15.3. The two eight and six year old maternal half-sisters were raised as foster children. 2. Clinical reports Written informed consent was obtained from the patients' surrogates. 2.1. Clinical description of the family The two affected girls are two of three maternal half-sisters e each with a different father - born within three years. The mother was referred to as having a reduced intelligence in the borderline range and having not obtained any school degree. Moreover, she was reported as an alcoholic and drug addict during all three pregnancies. All three children were withdrawn from the mother shortly after birth due to her dissocial and neglecting behavior and
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M. Eggert et al. / European Journal of Medical Genetics 59 (2016) 179e182
have been raised as foster children. The third, allegedly normal 7 year old half-sister and the mother of the three children were not presented in our department and no genetic analysis was performed. 2.2. Patient 1 The eight year old index patient described in detail here is the oldest of the three daughters. She was referred to our human genetics department due to intelligence deficit with rather low estimated IQ, disorder of speech development, behavioral problems and minor dysmorphic facial signs. An early global developmental delay including motor and speech delays were documented. The language and speech development was not only delayed but was also abnormal regarding typical developmental stages. Further, an inborn complex cardiac defect with a CAVSD (combined atrioventricular septal defect) and double orifice mitral valve was surgically corrected at the age of 3 months. In addition, the girl suffered from episodes of severe constipation. The result of a colon biopsy could not confirm a possible diagnosis of Hirschsprung's disease. Dysmorphic signs in the index patient were a broad nasal bridge, hypertelorism, short palpebral fissures, epicanthal folds, slightly deep set ears, widely spaced teeth, broad based tapered fingers, bilateral clinodactyly of big toes and fifth toes and bilateral position anomalies of toes with overriding second and fifth toes. Furthermore, pelvic obliquity, genua valga and flat feet were observed (Fig. 1). 2.3. Patient 2 The index patient's 6 year old half-sister showed similar facial features as well as global developmental delay with especially
pronounced disturbance of speech development and behavioral problems like low frustration tolerance and temper tantrums. However, organ malformations were not observed. At the time of human genetic examination a still not normally developed language was obvious. The intellectual ability had not yet been determined, but by estimation was in the borderline or lower normal range. Dysmorphic signs comprised a flat nasal bridge with wide intercanthal distance, epicanthic folds, relatively short palpebral fissures, large and slightly deep set ears, prognathism, dental diastema, short tongue ligament with fixation of the tip of the tongue, broad based tapered fingers with hyperextensibility of the interphalangeal joints, minimal partial syndactyly of toes 2e4 and 2e3, respectively, and position anomalies of toes with overriding 3rd toes and subduction and clinodactyly of fifth toes on both feet.
3. Genetic testing Conventional chromosome analysis in the index patient revealed a normal 46, XX karyotype; fragile X-Syndrome was excluded by FMR1 gene diagnostics. Array-CGH in the index patient revealed a microdeletion 10p15.3 (minimal deletion size of 334,51 kb). An additional intragenic microdeletion within CLK4 gene in 5q35.3 was classified as a variant of unknown significance (arr[hg19] 5q35.3(178,045,689e178,092,106)x1, 10p15.3(116,476e450,983) x1) (annotation to LOVD database patient ID #00057174). Array-CGH in the 6 year old half-sister revealed the same 10p15.3 microdeletion found in the index patient (arr[hg19] 10p15.3(116,476e450,983)x1) (Fig. 2).
Fig. 1. a, b and c: The eight year old index patient exhibits mild facial dysmorphy with broad flat nasal bridge, hypertelorism, epicanthal folds, short palpebral fissures, slightly deep set ears, and dental diastema. d: Bilateral flat feet, mild genua valga and minor body asymmetry with pelvic obliquity. e: broad based tapered fingers. f and g: clinodactyly of both big toes and position anomalies of toes with overriding fifth and second toes and slightly subducted toes 2 and 3.
M. Eggert et al. / European Journal of Medical Genetics 59 (2016) 179e182
181
Fig. 2. a) FISH result from blood lymphocytes of the index patient showing only one signal for the subtelomeric probe TelVys 10p (green), indicating terminal chromosome 10p deletion b) and c) Array-CGH result of chromosome 10 from patient 1 and 2 (region shown: chromosome 10 ptel to 4 MB). d) Comparison of deletion sizes in the reported familial case with the group of small 10p15.3 microdeletions reported by DeScipio et al. (2012).
4. Discussion 10p15.3 microdeletion syndrome has just recently been discovered. The clinical phenotype so far is based on a small number of 21 published patients, therefore only limited information regarding the possible phenotypic spectrum is available (DeScipio et al., 2012; Vargiami et al., 2014). The two familial patients presented here provide additional information, showing specific dysmorphology, heart defect, as well as cognitive and behavioral problems, global developmental delay and in particular a remarkable disturbance of speech development. The family constellation indicates a maternally transmitted microdeletion syndrome. The reported information on the mother likewise hints to cognitive and behavioral problems being in accordance with microdeletion 10p15.3 pathology. The findings in the two halfsisters correspond with the major characteristics of previously published patients. These characteristics include intellectual deficits or developmental delay in all affected individuals, and in particular problems of speech development, being observed in at least 10 patients (DeScipio et al., 2012). Further, identical dysmorphisms were seen in both children, displaying a broad flat nasal bridge with wide intercanthal distance (true hypertelorism confirmed only in one), short palpebral fissures, epicanthal folds and dental diastema, broad based tapered fingers, and similar
position anomalies as well as clinodactyly of toes. Shared facial phenotypes with published patients include a broad nasal bridge, hypertelorism, and epicanthal folds as recurrent signs of a possibly characteristic facial phenotype. In addition, short palpebral fissures were reported in at least one previously published patient. Finally, digital and toe anomalies, especially overriding toes were also present in some of the published patients (Table 1). Discordant findings in our patients were a severe congenital heart failure (CAVSD) in combination with malformation of the mitral valve (double orifice mitral valve) in the index patient, as well as severe lifelong constipation problems, and several orthopedic or skeletal anomalies with genua valga, pelvic obliquity and flat feet. On the other hand, prognathism, short tongue ligament, hyperextensibility of interphalangeal joints, and partial syndactyly of toes were only seen in patient 2. Of these findings severe constipation as well as congenital heart or cardiac valve malformation have already been reported each in two published patients (constipation in patients 2 and 9, heart/ valve malformation in patients 1 and 17 described by DeScipio et al., 2012; hyperextensibility of hands and partial syndactyly of toes were seen in one published patient) (patient 10 described by DeScipio et al., 2012) (Table 1). Congenital heart malformation (bicuspid aortic valve, foramen ovale) was present in two other patients described by DeScipio
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M. Eggert et al. / European Journal of Medical Genetics 59 (2016) 179e182
Table 1 Summary of clinical findings from our patients compared with published patients.
Motor delay Speech delay/language disorder Behavioral symptoms Intellectual disability Epicanthal folds Wide intercanthal distance/wide nasal bridge Short palpebral fissures Dental diastema Prognathism Short tongue ligament Tapered fingers Overriding toes Partial syndactyly of toes Clinodactyly of toes Flat feet Cardiac anomalies Genua valga Pelvic obliquity Constipation Susceptibility to infection
Index patient
Index patient's sister
12 patients DeScipio et al. (2012)
Monozygotic twins Vargiami et al. (2014)
X X X X X X X X no no X X no X X X X X X X
X X X (X) X X X X X X X X X X X no no no no no
at least 10 at least 10 at least 5 at least 5 at least 5 at least 4 1 not reported not reported not reported 1 1 1 2 1 at least 2 not reported not reported at least 2 1
X unknown unknown unknown not reported not reported not reported not reported not reported not reported unknown no no no unknown no not reported not reported no X
et al. (2012). Congenital heart defects may thus represent a variable symptom of the microdeletion 10p15.3 phenotype. On the other hand, maternal alcohol abuse, probably also during the pregnancies, was reported in our family. Heart malformations and facial dysmorphism as observed in patient 1 are as well typical features of alcohol embryopathy. However, fetal alcohol syndrome usually results from severe maternal alcohol abuse. Thus, an alcohol embryopathy in only the first and the third but not in the second of the three siblings born within narrow time frame appears less likely. The microdeletion in the presented family concerns a rather small terminal region of chromosome 10p15.3 encompassing only the gene ZMYND11 (also known as BS69) and part of the DIP2C gene. The microdeletion is thus located within the common deleted region of formerly reported patients by DeScipio et al. (2012) and Vargiami et al. (2014), who predominantly carry larger terminal or proximal deletions affecting 10p15.3. The high overlap of symptoms in our familial patients with major symptoms of formerly reported microdeletion 10p15.3 individuals strengthens the assumption made by DeScipio et al. (2012) that haploinsufficiency of ZMYND11 and/or DIP2C may be solely responsible for the major microdeletion 10p15.3 syndrome phenotype. There is at least one patient annotated in the DECIPHER database carrying a rather small microdeletion covering only the ZMYND11 gene. This patient showed delayed speech and language development accompanied by heart abnormality, and e among other physical signs e facial dysmorphism and overriding toes almost identically found in our patients. This renders ZMYND11 a major candidate gene for the microdeletion 10p15.3 symptoms (DECIPHER database patient ID 246177). DIP2C is classified as member of the disco-interacting protein homology 2 family of so far unknown function in humans. ZMYND11 is discussed as a potential chromatin regulator and was shown to be involved in RNA alternative splicing (Guo et al., 2014; Wen et al., 2014). However, the roles of ZMYND11 and DIP2C relating to symptoms of 10p15.3 microdeletion syndrome remain to be elucidated. In summary the observed symptoms of intellectual deficit, global developmental delay, disorder of speech development, behavioral problems, and facial phenotype can be considered as phenotypic core characteristics of microdeletion 10p15.3
syndrome. Dental diastema, prognathism, short tongue ligament, genua valga and pelvic obliquity are first reported in one or both of our presented familial patients and might represent sporadic features of microdeletion 10p15.3 syndrome thus broadening the phenotypic spectrum. Furthermore, congenital heart/valve malformation might be a syndromic sign for microdeletion 10p15.3. Moreover, the microdeletion 10p15.3 syndrome may be associated with constipation and short palpebral fissures. The reported patients corroborate and extend the so far described phenotype of the microdeletion 10p15.3 syndrome. Conflicts of interest None. Acknowledgments We thank the family for their participation in this study. References Carvill, G.L., Mefford, H.C., 2013. Microdeletion syndromes. Curr. Opin. Genet. Dev. 23, 232e239. DeScipio, C., Conlin, L., Rosenfeld, J., Tepperberg, J., Pasion, R., Patel, A., McDonald, M.T., Aradhya, S., Ho, D., Goldstein, J., McGuire, M., Mulchandani, S., Medne, L., Rupps, R., Serrano, A.H., Thorland, E.C., Tsai, A.C., Hilhorst-Hofstee, Y., Ruivenkamp, C.A., Van Esch, H., Addor, M.C., Martinet, D., Mason, T.B., Clark, D., Spinner, N.B., Krantz, I.D., 2012. Subtelomeric deletion of chromosome 10p15.3: clinical findings and molecular cytogenetic characterization. Am. J. Med. Genet. Part A 158A, 2152e2161. Guo, R., Zheng, L., Park, J.W., Lv, R., Chen, H., Jiao, F., Xu, W., Mu, S., Wen, H., Qiu, J., Wang, Z., Yang, P., Wu, F., Hui, J., Fu, X., Shi, X., Shi, Y.G., Xing, Y., Lan, F., Shi, Y., 2014. BS69/ZMYND11 reads and connects histone H3.3 lysine 36 trimethylation-decorated chromatin to regulated pre-mRNA processing. Mol. Cell 56, 298e310. Vargiami, E., Ververi, A., Kyriazi, M., Papathanasiou, E., Gioula, G., Gerou, S., AlMutawa, H., Kambouris, M., Zafeiriou, D.I., 2014. Severe clinical presentation in monozygotic twins with 10p15.3 microdeletion syndrome. Am. J. Med. Genet. Part A 164A, 764e768. Vissers, L.E., de Vries, B.B., Veltman, J.A., 2010. Genomic microarrays in mental retardation: from copy number variation to gene, from research to diagnosis. J. Med. Genet. 47, 289e297. Wen, H., Li, Y., Li, H., Shi, X., 2014. ZMYND11: an H3.3-specific reader of H3K36me3. Cell Cycle Georget. Tex. 13, 2153e2154.
Contents lists available at ScienceDirect
European Journal of Medical Genetics journal homepage: http://www.elsevier.com/locate/ejmg
A new familial case of microdeletion syndrome 10p15.3 Marlene Eggert a, *, Stefan Müller a, Uwe Heinrich b, Yasmin Mehraein a a b
Institute of Human Genetics, University Hospital, LMU Munich, Munich, Germany Center for Human Genetics and Laboratory Medicine, Dres. Klein and Rost, Martinsried, Germany
a r t i c l e i n f o
a b s t r a c t
Article history: Received 23 December 2015 Received in revised form 9 February 2016 Accepted 21 February 2016 Available online 24 February 2016
In 2012 a small terminal deletion in the short arm of chromosome 10 in the region 10p15.3 was reported as a novel microdeletion syndrome. By now 21 patients, including a single familial case, have been reported. Characteristic findings comprise variable cognitive impairment or developmental delay, disorder of speech development, as well as various dysmorphic signs. We here report on a new patient, an eight year old girl, with a microdeletion syndrome 10p15.3. She is a foster child showing intellectual deficits, disorder of speech development, behavioral problems, congenital heart defect, and several dysmorphic signs. The same microdeletion was subsequently found in the six year old maternal half-sister, showing very similar developmental and cognitive issues, including major speech impairment. The mother has not obtained a school degree. She was described as being a dissocial person with severe alcohol abuse and showing minor cognitive disability. Thus inheritance of the microdeletion from a probably symptomatic mother can be assumed. The patients presented here add up to the as yet small number of reported cases of microdeletion 10p15.3 and thereby might help to establish a more comprehensive clinical spectrum of this rather newly discovered syndrome. © 2016 Elsevier Masson SAS. All rights reserved.
Keywords: Microdeletion 10p15.3 syndrome Language disorder
1. Introduction Besides monogenic defects and classical chromosomal aberrations submicroscopic chromosomal imbalances comprising microdeletions and microduplications account for a major group of clinically important genetic alterations. A number of previously well-defined genetic syndromes were identified as microdeletion or microduplication syndromes. The diagnostic use of array-CGH to address clinically unclear or nonspecific conditions, in particular syndromic intellectual disability, allows the identification of novel recurrent micro-imbalances representing new microdeletion/ microduplication syndromes (Carvill and Mefford, 2013; Vissers et al., 2010). Quite recently a small subgroup of patients with similar microdeletions in the short arm of chromosome 10 was defined as a new microdeletion syndrome 10p15.3. To date only 23 patients, and among them only one familial case, showing variable chromosomal breakpoints and deletion sizes, have been reported. Clinical data was available from only 15 of the 21 published patients (DeScipio et al., 2012; Vargiami et al., 2014). Characteristic clinical
* Corresponding author. Institute of Human Genetics, University Hospital of Ludwig-Maximilians-University Munich, Goethestr. 29, D-80336, Munich, Germany. E-mail address: [email protected] (M. Eggert). http://dx.doi.org/10.1016/j.ejmg.2016.02.008 1769-7212/© 2016 Elsevier Masson SAS. All rights reserved.
findings in affected individuals described so far comprised variable cognitive impairment or developmental delay, speech delay and disorder of speech development, as well as uncharacterized dysmorphic signs (DeScipio et al., 2012; Vargiami et al., 2014). However, this rather nonspecific phenotype still needs to be refined by adding detailed information from further patients. We here report on a new familial case of microdeletion syndrome 10p15.3. The two eight and six year old maternal half-sisters were raised as foster children. 2. Clinical reports Written informed consent was obtained from the patients' surrogates. 2.1. Clinical description of the family The two affected girls are two of three maternal half-sisters e each with a different father - born within three years. The mother was referred to as having a reduced intelligence in the borderline range and having not obtained any school degree. Moreover, she was reported as an alcoholic and drug addict during all three pregnancies. All three children were withdrawn from the mother shortly after birth due to her dissocial and neglecting behavior and
180
M. Eggert et al. / European Journal of Medical Genetics 59 (2016) 179e182
have been raised as foster children. The third, allegedly normal 7 year old half-sister and the mother of the three children were not presented in our department and no genetic analysis was performed. 2.2. Patient 1 The eight year old index patient described in detail here is the oldest of the three daughters. She was referred to our human genetics department due to intelligence deficit with rather low estimated IQ, disorder of speech development, behavioral problems and minor dysmorphic facial signs. An early global developmental delay including motor and speech delays were documented. The language and speech development was not only delayed but was also abnormal regarding typical developmental stages. Further, an inborn complex cardiac defect with a CAVSD (combined atrioventricular septal defect) and double orifice mitral valve was surgically corrected at the age of 3 months. In addition, the girl suffered from episodes of severe constipation. The result of a colon biopsy could not confirm a possible diagnosis of Hirschsprung's disease. Dysmorphic signs in the index patient were a broad nasal bridge, hypertelorism, short palpebral fissures, epicanthal folds, slightly deep set ears, widely spaced teeth, broad based tapered fingers, bilateral clinodactyly of big toes and fifth toes and bilateral position anomalies of toes with overriding second and fifth toes. Furthermore, pelvic obliquity, genua valga and flat feet were observed (Fig. 1). 2.3. Patient 2 The index patient's 6 year old half-sister showed similar facial features as well as global developmental delay with especially
pronounced disturbance of speech development and behavioral problems like low frustration tolerance and temper tantrums. However, organ malformations were not observed. At the time of human genetic examination a still not normally developed language was obvious. The intellectual ability had not yet been determined, but by estimation was in the borderline or lower normal range. Dysmorphic signs comprised a flat nasal bridge with wide intercanthal distance, epicanthic folds, relatively short palpebral fissures, large and slightly deep set ears, prognathism, dental diastema, short tongue ligament with fixation of the tip of the tongue, broad based tapered fingers with hyperextensibility of the interphalangeal joints, minimal partial syndactyly of toes 2e4 and 2e3, respectively, and position anomalies of toes with overriding 3rd toes and subduction and clinodactyly of fifth toes on both feet.
3. Genetic testing Conventional chromosome analysis in the index patient revealed a normal 46, XX karyotype; fragile X-Syndrome was excluded by FMR1 gene diagnostics. Array-CGH in the index patient revealed a microdeletion 10p15.3 (minimal deletion size of 334,51 kb). An additional intragenic microdeletion within CLK4 gene in 5q35.3 was classified as a variant of unknown significance (arr[hg19] 5q35.3(178,045,689e178,092,106)x1, 10p15.3(116,476e450,983) x1) (annotation to LOVD database patient ID #00057174). Array-CGH in the 6 year old half-sister revealed the same 10p15.3 microdeletion found in the index patient (arr[hg19] 10p15.3(116,476e450,983)x1) (Fig. 2).
Fig. 1. a, b and c: The eight year old index patient exhibits mild facial dysmorphy with broad flat nasal bridge, hypertelorism, epicanthal folds, short palpebral fissures, slightly deep set ears, and dental diastema. d: Bilateral flat feet, mild genua valga and minor body asymmetry with pelvic obliquity. e: broad based tapered fingers. f and g: clinodactyly of both big toes and position anomalies of toes with overriding fifth and second toes and slightly subducted toes 2 and 3.
M. Eggert et al. / European Journal of Medical Genetics 59 (2016) 179e182
181
Fig. 2. a) FISH result from blood lymphocytes of the index patient showing only one signal for the subtelomeric probe TelVys 10p (green), indicating terminal chromosome 10p deletion b) and c) Array-CGH result of chromosome 10 from patient 1 and 2 (region shown: chromosome 10 ptel to 4 MB). d) Comparison of deletion sizes in the reported familial case with the group of small 10p15.3 microdeletions reported by DeScipio et al. (2012).
4. Discussion 10p15.3 microdeletion syndrome has just recently been discovered. The clinical phenotype so far is based on a small number of 21 published patients, therefore only limited information regarding the possible phenotypic spectrum is available (DeScipio et al., 2012; Vargiami et al., 2014). The two familial patients presented here provide additional information, showing specific dysmorphology, heart defect, as well as cognitive and behavioral problems, global developmental delay and in particular a remarkable disturbance of speech development. The family constellation indicates a maternally transmitted microdeletion syndrome. The reported information on the mother likewise hints to cognitive and behavioral problems being in accordance with microdeletion 10p15.3 pathology. The findings in the two halfsisters correspond with the major characteristics of previously published patients. These characteristics include intellectual deficits or developmental delay in all affected individuals, and in particular problems of speech development, being observed in at least 10 patients (DeScipio et al., 2012). Further, identical dysmorphisms were seen in both children, displaying a broad flat nasal bridge with wide intercanthal distance (true hypertelorism confirmed only in one), short palpebral fissures, epicanthal folds and dental diastema, broad based tapered fingers, and similar
position anomalies as well as clinodactyly of toes. Shared facial phenotypes with published patients include a broad nasal bridge, hypertelorism, and epicanthal folds as recurrent signs of a possibly characteristic facial phenotype. In addition, short palpebral fissures were reported in at least one previously published patient. Finally, digital and toe anomalies, especially overriding toes were also present in some of the published patients (Table 1). Discordant findings in our patients were a severe congenital heart failure (CAVSD) in combination with malformation of the mitral valve (double orifice mitral valve) in the index patient, as well as severe lifelong constipation problems, and several orthopedic or skeletal anomalies with genua valga, pelvic obliquity and flat feet. On the other hand, prognathism, short tongue ligament, hyperextensibility of interphalangeal joints, and partial syndactyly of toes were only seen in patient 2. Of these findings severe constipation as well as congenital heart or cardiac valve malformation have already been reported each in two published patients (constipation in patients 2 and 9, heart/ valve malformation in patients 1 and 17 described by DeScipio et al., 2012; hyperextensibility of hands and partial syndactyly of toes were seen in one published patient) (patient 10 described by DeScipio et al., 2012) (Table 1). Congenital heart malformation (bicuspid aortic valve, foramen ovale) was present in two other patients described by DeScipio
182
M. Eggert et al. / European Journal of Medical Genetics 59 (2016) 179e182
Table 1 Summary of clinical findings from our patients compared with published patients.
Motor delay Speech delay/language disorder Behavioral symptoms Intellectual disability Epicanthal folds Wide intercanthal distance/wide nasal bridge Short palpebral fissures Dental diastema Prognathism Short tongue ligament Tapered fingers Overriding toes Partial syndactyly of toes Clinodactyly of toes Flat feet Cardiac anomalies Genua valga Pelvic obliquity Constipation Susceptibility to infection
Index patient
Index patient's sister
12 patients DeScipio et al. (2012)
Monozygotic twins Vargiami et al. (2014)
X X X X X X X X no no X X no X X X X X X X
X X X (X) X X X X X X X X X X X no no no no no
at least 10 at least 10 at least 5 at least 5 at least 5 at least 4 1 not reported not reported not reported 1 1 1 2 1 at least 2 not reported not reported at least 2 1
X unknown unknown unknown not reported not reported not reported not reported not reported not reported unknown no no no unknown no not reported not reported no X
et al. (2012). Congenital heart defects may thus represent a variable symptom of the microdeletion 10p15.3 phenotype. On the other hand, maternal alcohol abuse, probably also during the pregnancies, was reported in our family. Heart malformations and facial dysmorphism as observed in patient 1 are as well typical features of alcohol embryopathy. However, fetal alcohol syndrome usually results from severe maternal alcohol abuse. Thus, an alcohol embryopathy in only the first and the third but not in the second of the three siblings born within narrow time frame appears less likely. The microdeletion in the presented family concerns a rather small terminal region of chromosome 10p15.3 encompassing only the gene ZMYND11 (also known as BS69) and part of the DIP2C gene. The microdeletion is thus located within the common deleted region of formerly reported patients by DeScipio et al. (2012) and Vargiami et al. (2014), who predominantly carry larger terminal or proximal deletions affecting 10p15.3. The high overlap of symptoms in our familial patients with major symptoms of formerly reported microdeletion 10p15.3 individuals strengthens the assumption made by DeScipio et al. (2012) that haploinsufficiency of ZMYND11 and/or DIP2C may be solely responsible for the major microdeletion 10p15.3 syndrome phenotype. There is at least one patient annotated in the DECIPHER database carrying a rather small microdeletion covering only the ZMYND11 gene. This patient showed delayed speech and language development accompanied by heart abnormality, and e among other physical signs e facial dysmorphism and overriding toes almost identically found in our patients. This renders ZMYND11 a major candidate gene for the microdeletion 10p15.3 symptoms (DECIPHER database patient ID 246177). DIP2C is classified as member of the disco-interacting protein homology 2 family of so far unknown function in humans. ZMYND11 is discussed as a potential chromatin regulator and was shown to be involved in RNA alternative splicing (Guo et al., 2014; Wen et al., 2014). However, the roles of ZMYND11 and DIP2C relating to symptoms of 10p15.3 microdeletion syndrome remain to be elucidated. In summary the observed symptoms of intellectual deficit, global developmental delay, disorder of speech development, behavioral problems, and facial phenotype can be considered as phenotypic core characteristics of microdeletion 10p15.3
syndrome. Dental diastema, prognathism, short tongue ligament, genua valga and pelvic obliquity are first reported in one or both of our presented familial patients and might represent sporadic features of microdeletion 10p15.3 syndrome thus broadening the phenotypic spectrum. Furthermore, congenital heart/valve malformation might be a syndromic sign for microdeletion 10p15.3. Moreover, the microdeletion 10p15.3 syndrome may be associated with constipation and short palpebral fissures. The reported patients corroborate and extend the so far described phenotype of the microdeletion 10p15.3 syndrome. Conflicts of interest None. Acknowledgments We thank the family for their participation in this study. References Carvill, G.L., Mefford, H.C., 2013. Microdeletion syndromes. Curr. Opin. Genet. Dev. 23, 232e239. DeScipio, C., Conlin, L., Rosenfeld, J., Tepperberg, J., Pasion, R., Patel, A., McDonald, M.T., Aradhya, S., Ho, D., Goldstein, J., McGuire, M., Mulchandani, S., Medne, L., Rupps, R., Serrano, A.H., Thorland, E.C., Tsai, A.C., Hilhorst-Hofstee, Y., Ruivenkamp, C.A., Van Esch, H., Addor, M.C., Martinet, D., Mason, T.B., Clark, D., Spinner, N.B., Krantz, I.D., 2012. Subtelomeric deletion of chromosome 10p15.3: clinical findings and molecular cytogenetic characterization. Am. J. Med. Genet. Part A 158A, 2152e2161. Guo, R., Zheng, L., Park, J.W., Lv, R., Chen, H., Jiao, F., Xu, W., Mu, S., Wen, H., Qiu, J., Wang, Z., Yang, P., Wu, F., Hui, J., Fu, X., Shi, X., Shi, Y.G., Xing, Y., Lan, F., Shi, Y., 2014. BS69/ZMYND11 reads and connects histone H3.3 lysine 36 trimethylation-decorated chromatin to regulated pre-mRNA processing. Mol. Cell 56, 298e310. Vargiami, E., Ververi, A., Kyriazi, M., Papathanasiou, E., Gioula, G., Gerou, S., AlMutawa, H., Kambouris, M., Zafeiriou, D.I., 2014. Severe clinical presentation in monozygotic twins with 10p15.3 microdeletion syndrome. Am. J. Med. Genet. Part A 164A, 764e768. Vissers, L.E., de Vries, B.B., Veltman, J.A., 2010. Genomic microarrays in mental retardation: from copy number variation to gene, from research to diagnosis. J. Med. Genet. 47, 289e297. Wen, H., Li, Y., Li, H., Shi, X., 2014. ZMYND11: an H3.3-specific reader of H3K36me3. Cell Cycle Georget. Tex. 13, 2153e2154.