Home About us Editorial board Ahead of print Current issue Search Archives Submit article Instructions Subscribe Contacts Login 
5 years IF: 1.036 (® Thomson Reuters)
IF 2016: 1.064 (® Thomson Reuters)
Total Cites: 7140
Follow Us
Follow Us
  • Users Online: 2623
  • Home
  • Print this page
  • Email this page

 Table of Contents  
ORIGINAL ARTICLE
Year : 2017  |  Volume : 130  |  Issue : 6  |  Page : 703-709

Clinical Auditory Phenotypes Associated with GATA3 Gene Mutations in Familial Hypoparathyroidism-deafness-renal Dysplasia Syndrome


1 Department of Otolaryngology Head and Neck Surgery, Institute of Otolaryngology, Chinese People's Liberation Army General Hospital, Beijing 100853; Department of Clinical Medicine, School of Medicine, Nankai University, Tianjin 300071, China
2 Beijing Genomics Institute, Shenzhen, Guangdong 518083, China
3 Department of Otolaryngology Head and Neck Surgery, Institute of Otolaryngology, Chinese People's Liberation Army General Hospital, Beijing 100853, China
4 Beijing Genomics Institute, Shenzhen, Guangdong 518083; James D. Watson Institute of Genome Sciences, Hangzhou, Zhejiang 310058, China

Date of Submission27-Oct-2016
Date of Web Publication6-Mar-2017

Correspondence Address:
Qiu-Ju Wang
Chinese People's Liberation Army Institute of Otolaryngology, Chinese People's Liberation Army General Hospital, 28 Fuxing Road, Beijing 100853
China
Login to access the Email id

Source of Support: None, Conflict of Interest: None


DOI: 10.4103/0366-6999.201600

Rights and Permissions
  Abstract 

Background: Hypoparathyroidism-deafness-renal dysplasia (HDR) syndrome is an autosomal dominant disorder primarily caused by haploinsufficiency of GATA binding protein 3 (GATA3) gene mutations, and hearing loss is the most frequent phenotypic feature. This study aimed at identifying the causative gene mutation for a three-generation Chinese family with HDR syndrome and analyzing auditory phenotypes in all familial HDR syndrome cases.
Methods: Three affected family members underwent otologic examinations, biochemistry tests, and other clinical evaluations. Targeted genes capture combining next-generation sequencing was performed within the family. Sanger sequencing was used to confirm the causative mutation. The auditory phenotypes of all reported familial HDR syndrome cases analyzed were provided.
Results: In Chinese family 7121, a heterozygous nonsense mutation c.826C>T (p.R276*) was identified in GATA3. All the three affected members suffered from sensorineural deafness and hypocalcemia; however, renal dysplasia only appeared in the youngest patient. Furthermore, an overview of thirty HDR syndrome families with corresponding GATA3 mutations revealed that hearing impairment occurred earlier in the younger generation in at least nine familial cases (30%) and two thirds of them were found to carry premature stop mutations.
Conclusions: This study highlights the phenotypic heterogeneity of HDR and points to a possible genetic anticipation in patients with HDR, which needs to be further investigated.

Keywords: GATA binding protein 3; Genetic Anticipation; Hypoparathyroidism-deafness-renal Dysplasia Syndrome


How to cite this article:
Wang L, Lin QF, Wang HY, Guan J, Lan L, Xie LY, Yu L, Yang J, Zhao C, Liang JL, Zhou HL, Yang HM, Xiong WP, Zhang QJ, Wang DY, Wang QJ. Clinical Auditory Phenotypes Associated with GATA3 Gene Mutations in Familial Hypoparathyroidism-deafness-renal Dysplasia Syndrome. Chin Med J 2017;130:703-9

How to cite this URL:
Wang L, Lin QF, Wang HY, Guan J, Lan L, Xie LY, Yu L, Yang J, Zhao C, Liang JL, Zhou HL, Yang HM, Xiong WP, Zhang QJ, Wang DY, Wang QJ. Clinical Auditory Phenotypes Associated with GATA3 Gene Mutations in Familial Hypoparathyroidism-deafness-renal Dysplasia Syndrome. Chin Med J [serial online] 2017 [cited 2017 Aug 20];130:703-9. Available from: http://www.cmj.org/text.asp?2017/130/6/703/201600


  Introduction Top


Hypoparathyroidism-deafness-renal dysplasia (HDR) syndrome (MIM 146255), also known as Barakat syndrome,[1] is a rare autosomal dominant disorder named from a triad of hypoparathyroidism, sensorineural deafness, and renal dysplasia.[2] The individuals affected by HDR syndrome have various heterogeneous clinical characteristics. Sensorineural deafness could be the most common clinical feature, while hypoparathyroidism and renal dysplasia were described by various expressions [3],[4],[5] and even could be asymptomatic, making a timely diagnosis of HDR syndrome more important.

GATA binding protein 3 (GATA3), a gene belonging to the family of zinc finger transcription factors and binding to the [A/T] GATA [A/G] consensus sequence, is the only reported gene responsible for this unusual developmental disease. Located on chromosome 10p15, GATA3 contains two N-terminal transactivating domains (TA1 and TA2) and two C-terminal zinc finger domains (ZnF1 and ZnF2), as shown in [Figure 1]. To date, more than fifty GATA3 mutations related with both sporadic and familial HDR syndrome have been reported, and GATA3 haploinsufficiency has been considered as the underlying mechanism.[6],[7] Compared with sporadic cases, familial cases provide us the opportunity to explore the inheritance pattern and to consider the possible genetic anticipation in patients with HDR.
Figure 1: Structure map of GATA3 gene: GATA3 contains 6 exons and the arrow denotes the mutation identified in family 7121 located within exon4; GATA3: GATA binding protein 3. N: N-terminus; TA: Transactivating domains; ZnF: Zinc fingers domains; C: C-terminus.

Click here to view


In the present study, we identified a nonsense mutation in GATA3[6] in a hearing impaired Chinese family with various clinical features of HDR syndrome by using targeted capture and next-generation sequencing (NGS). In addition, auditory phenotype in familial HDR syndrome associated with GATA3 mutation was analyzed by reviewing previous literatures.


  Methods Top


Patients

A 7-year-old boy (proband) came from Chinese family 7121, a three-generation family with a segregating autosomal dominant hearing loss (HL) as shown in [Figure 2], and four family members were recruited and gave written consent. This study was approved by the Ethics Committee of Chinese People's Liberation Army General Hospital.
Figure 2: Pedigree of a family with hypoparathyroidism-deafness-renal syndrome. The arrow denotes proband.

Click here to view


Clinical evaluations for parathyroid glands, renal, and auditory phenotypes

Their medical histories were collected by a questionnaire. Physical examination, otoscopy, immittance testing, pure tone audiometric examination, and speech audiometry were performed on the three affected members to evaluate the auditory conditions. The diagnosis of sensorineural hearing impairment was made according to the World Health Organization criteria available at http://www.who.int/. The degrees of HL were categorized as mild (26–40 dB HL), moderate (41–60 dB HL), severe (61–80 dB HL), and profound HL (>80 dB HL). A computed tomography (CT) scan for the temporal bone of both ears was also performed on the proband.

Peripheral blood and urine samples were collected to measure the parathyroidal and renal function. Biochemical laboratory tests included serum calcium, magnesium, phosphorus, and intact parathyroid hormone (iPTH) levels, plasma creatinine, and carbamide levels, whereas urinalysis, renal ultrasound, and nuclear examinations were applied to detect the renal anomalies.

Targeted sequencing and variation analysis

Genomic DNA was extracted from peripheral blood sample from the three affected members and one unaffected member. After the examination of DNA quality, Beijing Genomics Institute built the DNA libraries by following the Illumina's protocol, and then 307 deafness-related genes [Supplementary Table 1] including exons, splicing sites, and their flanking introns were captured by using a custom probe and sequenced by Illumina HiSeq2000 (Illumina, San Diego, CA, USA), which had been previously described.[8][Additional file 1]

The paired-end reads generated by sequencing were aligned to NCBI37/hg19 assembly by the Burrows-Wheeler Alignment Tool (version 0.7.10, http://bio-bwa.sourceforge.net/), and variant calling was performed by Genome Analysis Toolkit (version 3.3-0, https://software.broadinstitute.org/gatk/index.php).

Variants with allele frequencies higher than 5% in the 1000 Genomes Project and the local database were excluded. Splicing site, frameshift, and nonsense variants would be taken into further consideration. Moreover, SIFT (http://sift.jcvi.org/) and PolyPhen2 (http://genetics.bwh.harvard.edu/pph2/) softwares were used to evaluate the pathogenic possibility of missense variants. Sanger sequencing was performed to establish the co-segregation of the candidate gene mutations with the phenotype in the family members. A three-dimensional structure of GATA3 was built by Swiss-model (http://swissmodel.expasy.org/workspace/) and then visualized by Swiss-PdbViewer (version 4.1, http://spdbv.vital-it.ch/).

Analysis of familial cases and related mutations

Literature review was performed by searching EMBASE and PUBMED databases. The genotypes and auditory phenotypes of these familial HDR syndrome cases were summarized. Then, a comprehensive inter- and intra-family comparison of clinical deafness characteristics was performed.


  Results Top


Mutation detection and analysis

All the three hearing-impaired family members were identified to carry out the same GATA3 mutation. The heterozygous c.826C>T (NM_002051.2) is a nonsense mutation located within exon4 that resulted in a premature termination codon (R276*) predicted to lead to GATA3 haploinsufficiency [Figure 1] and [Figure 2]. Co-segregation of this mutation with the disease was confirmed by using Sanger sequencing as shown in [Figure 3]. The normal member among the siblings did not have the mutation, while the other three affected members were carrying the same nonsense mutation. Moreover, the absence of this mutation in the 1000 Genomes Project and 1751 ethnicity-matched normal hearing individuals further supported the pathogenicity.
Figure 3: Sanger sequencing results and the co-segregation of the mutation with the phenotype in the family members with hypoparathyroidism-deafness-renal syndrome. Red arrows denote GATA3 mutation c.826C>T (p.R276*). GATA3: GATA binding protein 3.

Click here to view


Clinical description

As shown in [Table 1] and [Figure 4], the three affected members in family 7121 had early-onset sensorineural deafness. The average hearing thresholds in the better ears of proband and his mother (II2) were 56 and 45 dB HL, respectively, belonging to moderate HL according to the grades of hearing impairment from the World Health Organization. However, grandmother of proband (I2) had profound hearing impairment with the average hearing threshold of 85 dB HL. The proband and his mother (II2) could communicate without any difficulty because their hearing disturbances were not severe. Temporal bone CT scans performed on the proband were normal.
Figure 4: Pure-tone audiograms of the three affected family members with GATA3 mutation p.R276*: blue represents left ear, red represents right ear. HL: Hearing loss; GATA3: GATA binding protein.

Click here to view
Table 1: Genetic and clinical characteristics in family 7121

Click here to view


The results of biochemistry tests are summarized in [Table 1]. Clinically, they all had no symptom for hypoparathyroidism, but the assessment showed hypocalcemia, lower iPTH level, and mild hyperphosphaturia. In contrast, the urinalysis of all the affected members revealed no abnormalities and indicated a normal renal function.

However, nephrosonography showed that the proband had left renal agenesis while the other two affected family members had normal bilateral kidneys without any detectable abnormality. Then, nuclear medical examination on the proband showed the normal renal function further.

Overview of familial hypoparathyroidism-deafness-renal dysplasia syndrome

The reported familial cases of HDR syndrome were summarized in [Table 2] by different mutations. A total of 30 families carrying various GATA3 abnormalities contained missense/nonsense mutations, small deletions and insertions (indels), splicing, and gross deletions. All the corresponding onset time and laterality of HL observed in the familial cases are shown in [Table 2]. Remarkably, nine parent-child pairs were proved to have hearing impairment earlier more than a decade or more severe in the younger generation, which was observed in 30% of all familial cases. There was a significant difference in the types of the mutations in these nine familial cases, indicating a high proportion of premature stop mutations as much as 66.7%.
Table 2: Review of genotype and auditory phenotypes in familial hypoparathyroidism-deafness-renal syndrome

Click here to view



  Discussion Top


In the present study, a heterozygous GATA3 nonsense mutation c.826C>T (p. R276*) was identified in a Chinese HDR family 7121 by applying a combination of the target deafness genes capture and NGS. Initially, all the affected members from three generations came to consult for their autosomal dominant hearing disturbances. Then, HDR syndrome was diagnosed precisely and effectively by using advanced genetic testing technology although there was no symptom of hypocalcemia and renal agenesis. The mutation c.826C>T (p.R276*) reported in the present study had been identified in a family 12/99 by Van Esch et al.[6] in the year 2000. The identification of R276* in the Chinese family 7121 further ensured its pathogenic possibility in HDR syndrome: (1) sanger sequencing confirmed the co-segregation of this mutation with the phenotype in Chinese family 7121, and this specific mutation was absent in both the 1000 genomes and 1751 ethnicity-matched controls; (2) the location of mutation c.826C>Tin GATA3 was visualized clearly and this nonsense mutation resulted in truncating GATA3 protein completely by losing both ZnF1 and ZnF2 domains [Figure 1] and [Figure 5]. Notably, the two zinc fingers domains were described to be necessary for GATA3 protein in binding to DNA as well as the stabilization of binding function.[7] Further functional studies demonstrated that cochlear wiring and postsynaptic differentiation were disrupted without normal GATA3 expression.[25],[26]
Figure 5: Three-dimensional structure of GATA3 wild-type created by SWISS-MODEL mutation p.R276* causing loss of both ZnF1 and ZnF2 domains. GATA3: GATA binding protein 3.

Click here to view


Clinical spectrum of HDR syndrome includes hypoparathyroidism, sensorineural deafness, and renal dysplasia. As previously reported, about 62.3% of the patients had complete clinical triad in HDR syndrome.[27] The patients carrying the same mutation p.R276* in another European family displayed different clinical phenotypes. Contrary to the Chinese family 7121, the two affected members in 12/99 family did not have any renal anomaly.[6] Moreover, clinical features of patients with HDR syndrome were variable even in the same Chinese family 7121, which was also observed in other cases.[18],[19],[27] In fact, due to the high heterogeneous expression in individuals, it is not easy for clinicians to make a distinction between human nonsyndromic and syndromic hereditary HL such as HDR syndrome. Therefore, NGS technology could be a powerful tool in early diagnosis and appropriate management.

Genetic anticipation is a biological symptom in successive generation, in which the pedigrees appear to have earlier onset or more severity in the disease tendency. Considering the existing ascertainment bias, we insist on the presence of genetic anticipation that only a different decade is significant and reveal that at least 30% of familial cases (a total of 9 families) showed the possible genetic anticipation, which might be one of the characteristics of familial HDR syndrome. This information is especially important for assisting with family planning in genetic consulting. To our knowledge, a number of genetic diseases such as  Charcot-Marie-Tooth disease More Details,[28] Lynch syndrome,[29] and familial essential tremor [30] have been recognized with anticipation in the different mechanisms [31],[32] including trinucleotide repeat expansion, telomeric dysfunction as well as epigenetic factors. Regarding the study, GATA3 mutation analysis in [Table 2] reflected a high proportion of premature stop mutations in familial patients with the possible genetic anticipation, which might be associated with the potential mechanism.

In conclusion, we have described a three-generation hearing impaired family with GATA3 nonsense mutation p.R276*, which was identified in Chinese population for the first time by targeted genes capture and NGS technology. An overview of familial cases revealed a decrease in the age at onset of deafness or more severity between generations in 30% of families, indicating the presence of possible anticipation. Further studies are needed to elucidate the molecular mechanisms of this phenomenon in HDR syndrome.

Supplementary information is linked to the online version of the paper on the Chinese Medical Journal website.

Financial support and sponsorship

This work was supported by grants from the National Natural Science Foundation of China (No. 81530032), The National Key Basic Research Program of China (No. 2014CB943001), and The China Postdoctoral Science Foundation (No. 2015M572766 and No. 2015M572690).

Conflicts of interest

There are no conflicts of interest.

 
  References Top

1.
Barakat AY, D'Albora JB, Martin MM, Jose PA. Familial nephrosis, nerve deafness, and hypoparathyroidism. J Pediatr 1977;91:61-4. doi: 10.1016/S0022-3476(77)80445-9.  Back to cited text no. 1
    
2.
Upadhyay J, Steenkamp DW, Milunsky JM. The syndrome of hypoparathyroidism, deafness, and renal anomalies. Endocr Pract 2013;19:1035-42. doi: 10.4158/EP13050.RA.  Back to cited text no. 2
[PUBMED]    
3.
Van Esch H, Devriendt K. Transcription factor GATA3 and the human HDR syndrome. Cell Mol Life Sci 2001;58:1296-300. doi: 10.1007/PL00000940.  Back to cited text no. 3
[PUBMED]    
4.
Chenouard A, Isidor B, Allain-Launay E, Moreau A, Le Bideau M, Roussey G. Renal phenotypic variability in HDR syndrome: Glomerular nephropathy as a novel finding. Eur J Pediatr 2013;172:107-10. doi: 10.1007/s00431-012-1845-y.  Back to cited text no. 4
[PUBMED]    
5.
Al-Shibli A, Al Attrach I, Willems PJ. Novel DNA mutation in the GATA3 gene in an Emirati boy with HDR syndrome and hypomagnesemia. Pediatr Nephrol 2011;26:1167-70. doi: 10.1007/s00467-011-1835-8.  Back to cited text no. 5
[PUBMED]    
6.
Van Esch H, Groenen P, Nesbit MA, Schuffenhauer S, Lichtner P, Vanderlinden G, et al. GATA3 haplo-insufficiency causes human HDR syndrome. Nature 2000;406:419-22. doi: 10.1038/35019088.  Back to cited text no. 6
[PUBMED]    
7.
Ali A, Christie PT, Grigorieva IV, Harding B, Van Esch H, Ahmed SF, et al. Functional characterization of GATA3 mutations causing the hypoparathyroidism-deafness-renal (HDR) dysplasia syndrome: Insight into mechanisms of DNA binding by the GATA3 transcription factor. Hum Mol Genet 2007;16:265-75. doi: 10.1093/hmg/ddl454.  Back to cited text no. 7
    
8.
Wang HY, Zhao YL, Liu Q, Yuan H, Gao Y, Lan L, et al. Identification of two disease-causing genes TJP2 and GJB2 in a Chinese family with unconditional autosomal dominant nonsyndromic hereditary hearing impairment. Chin Med J 2015;128:3345-51. doi: 10.4103/0366-6999.171440.  Back to cited text no. 8
[PUBMED]  [Full text]  
9.
Lin YH, Wu CC, Hsu TY, Chiu WY, Hsu CJ, Chen PL. Identification of a novel GATA3 mutation in a deaf Taiwanese family by massively parallel sequencing. Mutat Res 2015;771:1-5. doi: 10.1016/j.mrfmmm.2014.11.001.  Back to cited text no. 9
[PUBMED]    
10.
Zhu ZY, Zhou QL, Ni SN, Gu W. GATA3 mutation in a family with hypoparathyroidism, deafness and renal dysplasia syndrome. World J Pediatr 2014;10:278-80. doi: 10.1007/s12519-014-0505-x.  Back to cited text no. 10
[PUBMED]    
11.
Adachi M, Tachibana K, Asakura Y, Tsuchiya T. A novel mutation in the GATA3 gene in a family with HDR syndrome (Hypoparathyroidism, sensorineural Deafness and Renal anomaly syndrome). J Pediatr Endocrinol Metab 2006;19:87-92. doi: 10.1515/JPEM.2006.19.1.87.  Back to cited text no. 11
[PUBMED]    
12.
Nesbit MA, Bowl MR, Harding B, Ali A, Ayala A, Crowe C, et al. Characterization of GATA3 mutations in the hypoparathyroidism, deafness, and renal dysplasia (HDR) syndrome. J Biol Chem 2004;279:22624-34. doi: 10.1074/jbc.M401797200.  Back to cited text no. 12
[PUBMED]    
13.
Higuchi Y, Hasegawa K, Yamashita M, Fujii Y, Tanaka H, Tsukahara H. HDR syndrome in a Japanese girl with biliary atresia: A case report. BMC Pediatr 2016;16:14. doi: 10.1186/s12887-016-0550-9.  Back to cited text no. 13
    
14.
Muroya K, Hasegawa T, Ito Y, Nagai T, Isotani H, Iwata Y, et al. GATA3 abnormalities and the phenotypic spectrum of HDR syndrome. J Med Genet 2001;38:374-80. doi: 10.1136/jmg.38.6.374.  Back to cited text no. 14
[PUBMED]    
15.
Zahirieh A, Nesbit MA, Ali A, Wang K, He N, Stangou M, et al. Functional analysis of a novel GATA3 mutation in a family with the hypoparathyroidism, deafness, and renal dysplasia syndrome. J Clin Endocrinol Metab 2005;90:2445-50. doi: 10.1210/jc.2004-1969.  Back to cited text no. 15
[PUBMED]    
16.
Belge H, Dahan K, Cambier JF, Benoit V, Morelle J, Bloch J, et al. Clinical and mutational spectrum of hypoparathyroidism, deafness and renal dysplasia syndrome. Nephrol Dial Transplant 2016. pii: gfw271. doi: 10.1093/ndt/gfw271.  Back to cited text no. 16
    
17.
Okawa T, Yoshida M, Usui T, Kudou T, Iwasaki Y, Fukuoka K, et al. A novel loss-of-function mutation of GATA3 (p.R299Q) in a Japanese family with Hypoparathyroidism, Deafness, and Renal Dysplasia (HDR) syndrome. BMC Endocr Disord 2015;15:66. doi: 10.1186/s12902-015-0065-7.  Back to cited text no. 17
[PUBMED]    
18.
Nakamura A, Fujiwara F, Hasegawa Y, Ishizu K, Mabe A, Nakagawa H, et al. Molecular analysis of the GATA3 gene in five Japanese patients with HDR syndrome. Endocr J 2011;58:123-30. doi: 10.1507/endocrj.K10E-246.  Back to cited text no. 18
    
19.
Chiu WY, Chen HW, Chao HW, Yann LT, Tsai KS. Identification of three novel mutations in the GATA3 gene responsible for familial hypoparathyroidism and deafness in the Chinese population. J Clin Endocrinol Metab 2006;91:4587-92. doi: 10.1210/jc.2006-0864.  Back to cited text no. 19
[PUBMED]    
20.
Hernández AM, Villamar M, Roselló L, Moreno-Pelayo MA, Moreno F, Del Castillo I. Novel mutation in the gene encoding the GATA3 transcription factor in a Spanish familial case of hypoparathyroidism, deafness, and renal dysplasia (HDR) syndrome with female genital tract malformations. Am J Med Genet A 2007;143A:757-62. doi: 10.1002/ajmg.a.31617.  Back to cited text no. 20
    
21.
Mino Y, Kuwahara T, Mannami T, Shioji K, Ono K, Iwai N. Identification of a novel insertion mutation in GATA3 with HDR syndrome. Clin Exp Nephrol 2005;9:58-61. doi: 10.1007/s10157-004-0327-6.  Back to cited text no. 21
    
22.
Shim YS, Choi W, Hwang IT, Yang S. Hypoparathyroidism, sensorineural deafness, and renal dysgenesis syndrome with a GATA3 mutation. Ann Pediatr Endocrinol Metab 2015;20:59-63. doi: 10.6065/apem.2015.20.1.59.  Back to cited text no. 22
    
23.
van Beelen E, Leijendeckers JM, Admiraal RJ, Huygen PL, Hoefsloot LH, Pennings RJ, et al. Audiometric characteristics of a dutch family with a new mutation in GATA3 causing HDR syndrome. Audiol Neurootol 2014;19:106-14. doi: 10.1159/000356303.  Back to cited text no. 23
    
24.
Fukami M, Muroya K, Miyake T, Iso M, Kato F, Yokoi H, et al. GATA3 abnormalities in six patients with HDR syndrome. Endocr J 2011;58:117-21. doi: 10.1507/endocrj.K10E-234.  Back to cited text no. 24
    
25.
Appler JM, Lu CC, Druckenbrod NR, Yu WM, Koundakjian EJ, Goodrich LV. Gata3 is a critical regulator of cochlear wiring. J Neurosci 2013;33:3679-91. doi: 10.1523/JNEUROSCI.4703-12.2013.  Back to cited text no. 25
    
26.
Yu WM, Appler JM, Kim YH, Nishitani AM, Holt JR, Goodrich LV. A Gata3-Mafb transcriptional network directs post-synaptic differentiation in synapses specialized for hearing. Elife 2013;2:e01341. doi: 10.7554/eLife.01341.  Back to cited text no. 26
    
27.
Ferraris S, Del Monaco AG, Garelli E, Carando A, De Vito B, Pappi P, et al. HDR syndrome: A novel “de novo” mutation in GATA3 gene. Am J Med Genet A 2009;149A:770-5. doi: 10.1002/ajmg.a.32689.  Back to cited text no. 27
    
28.
Kovach MJ, Campbell KC, Herman K, Waggoner B, Gelber D, Hughes LF, et al. Anticipation in a unique family with Charcot-Marie-Tooth syndrome and deafness: Delineation of the clinical features and review of the literature. Am J Med Genet 2002;108:295-303. doi: 10.1002/ajmg.10223.  Back to cited text no. 28
    
29.
Boonstra PS, Gruber SB, Raymond VM, Huang SC, Timshel S, Nilbert M, et al. A review of statistical methods for testing genetic anticipation: Looking for an answer in Lynch syndrome. Genet Epidemiol 2010;34:756-68. doi: 10.1002/gepi.20534.  Back to cited text no. 29
    
30.
Louis ED, Hernandez N, Rabinowitz D, Ottman R, Clark LN. Predicting age of onset in familial essential tremor: How much does age of onset run in families? Neuroepidemiology 2013;40:269-73. doi: 10.1159/000345253.  Back to cited text no. 30
    
31.
Seguí N, Pineda M, Guinó E, Borràs E, Navarro M, Bellido F, et al. Telomere length and genetic anticipation in Lynch syndrome. PLoS One 2013;8:e61286. doi: 10.1371/journal.pone.0061286.  Back to cited text no. 31
    
32.
Nilbert M, Timshel S, Bernstein I, Larsen K. Role for genetic anticipation in Lynch syndrome. J Clin Oncol 2009;27:360-4. doi: 10.1200/JCO.2008.16.1281.  Back to cited text no. 32
    


    Figures

  [Figure 1], [Figure 2], [Figure 3], [Figure 4], [Figure 5]
 
 
    Tables

  [Table 1], [Table 2]



 

Top
 
 
  Search
 
Similar in PUBMED
   Search Pubmed for
   Search in Google Scholar for
 Related articles
Access Statistics
Email Alert *
Add to My List *
* Registration required (free)

 
  In this article
Abstract
Introduction
Methods
Results
Discussion
References
Article Figures
Article Tables

 Article Access Statistics
    Viewed226    
    Printed4    
    Emailed0    
    PDF Downloaded54    
    Comments [Add]    

Recommend this journal




京ICP备05052599号