1.Phenotype and genotype analysis of a pedigree affected with Joubert syndrome due to variant of TMEM237 gene.
Shandan CUI ; Haijuan LOU ; Haijun YIN ; Fangfang GENG ; Ning LI ; Lirong MA
Chinese Journal of Medical Genetics 2021;38(12):1211-1215
OBJECTIVE:
To explore the pathogenesis of two siblings (including a fetus) from a pedigree affected with Joubert syndrome.
METHODS:
Peripheral blood samples of the proband and his parents as well as amniotic fluid and abortion tissues of the fetus were collected. Part of the samples were used for the extraction of DNA, and whole exome sequencing (WES) was carried out to screen potential variants in the proband and his parents. Suspected variants were subjected to bioinformatics analysis with consideration of the clinical phenotype, and were verified by Sanger sequencing of the proband, fetus and their parents.The remainders were used for the extraction of RNA, and the mechanism of splicing variant was validated by reverse transcription-PCR (RT-PCR).
RESULTS:
WES showed that both patients have carried c.175C>T (p.R59X) and c.553+1G>A compound heterozygous variants of the TMEM237 gene. Among these, c.175C>T was a nonsense mutation inherited from the asymptomatic mother, while c.553+1G>A was an alternative splicing mutation inherited from the asymptomatic father. RT-PCR showed that this variant has resulted in aberrant splicing by exon skipping.
CONCLUSION
The compound heterozygous variants of the TMEM237 gene probably underlay the etiology of Joubert syndrome in this pedigree. Above finding has enriched the phenotype and variant spectrum of the TMEM237 gene, and facilitated genetic counseling and prenatal diagnosis for the family.
Abnormalities, Multiple/genetics*
;
Cerebellum/abnormalities*
;
Eye Abnormalities
;
Female
;
Genotype
;
Humans
;
Kidney Diseases, Cystic
;
Mutation
;
Pedigree
;
Phenotype
;
Pregnancy
;
Retina/abnormalities*
2.Unilateral Peters' Anomaly with Chorioretinal Coloboma in the Other Eye.
Dooyoung CHO ; Donggyu CHOI ; Wooho NAM
Korean Journal of Ophthalmology 2011;25(5):352-354
An 18-year-old man presented with poor vision in both eyes that had been present since birth. Central corneal opacity and inferior peripheral sclerocornea with iridocorneal adhesion were observed upon anterior segment examination of the left eye. A coloboma of the iris was observed in the patient's right eye, which manifested as a small notch in the inferior pupillary margin and cataract. Fundus examination of the right eye showed a large inferior chorioretinal coloboma involving the optic disc and macula. It is essential to examine the fundus in detail, if possible, in cases of Peters' anomaly, because these patients may have congenital anomalies such as chorioretinal coloboma.
*Abnormalities, Multiple
;
Adolescent
;
Anterior Eye Segment/abnormalities
;
Choroid/*abnormalities
;
Coloboma/*diagnosis
;
Corneal Opacity/*diagnosis
;
Diagnosis, Differential
;
Eye Abnormalities/*diagnosis
;
Humans
;
Male
;
Microscopy, Acoustic
;
Optic Nerve/abnormalities
;
Retina/*abnormalities
3.Unilateral Peters' Anomaly with Chorioretinal Coloboma in the Other Eye.
Dooyoung CHO ; Donggyu CHOI ; Wooho NAM
Korean Journal of Ophthalmology 2011;25(5):352-354
An 18-year-old man presented with poor vision in both eyes that had been present since birth. Central corneal opacity and inferior peripheral sclerocornea with iridocorneal adhesion were observed upon anterior segment examination of the left eye. A coloboma of the iris was observed in the patient's right eye, which manifested as a small notch in the inferior pupillary margin and cataract. Fundus examination of the right eye showed a large inferior chorioretinal coloboma involving the optic disc and macula. It is essential to examine the fundus in detail, if possible, in cases of Peters' anomaly, because these patients may have congenital anomalies such as chorioretinal coloboma.
*Abnormalities, Multiple
;
Adolescent
;
Anterior Eye Segment/abnormalities
;
Choroid/*abnormalities
;
Coloboma/*diagnosis
;
Corneal Opacity/*diagnosis
;
Diagnosis, Differential
;
Eye Abnormalities/*diagnosis
;
Humans
;
Male
;
Microscopy, Acoustic
;
Optic Nerve/abnormalities
;
Retina/*abnormalities
4.Phenotypic analysis and variant identification of a fetus with Joubert syndrome 17.
Yan ZHAO ; Yanhui ZHAO ; Yuan LYU ; Hong PANG
Chinese Journal of Medical Genetics 2021;38(9):841-844
OBJECTIVE:
To analyze the phenotype and genetic variant of a fetus with dysplasia of cerebellar vermis.
METHODS:
Gestational status and family history of the gravida was taken in combination with the imaging results of the fetus. Following elected abortion, fetal tissue and peripheral blood samples of the couple were collected for the extraction of genome DNA. Whole exome sequencing was carried out to screen potential variant associated with the phenotype of the proband. Specific PCR primers were designed to verify the results by Sanger sequencing.
RESULTS:
Prenatal ultrasound revealed that the fetal vermis cerebellum was poorly developed, which was similar to the previous pregnancy. Whole exome sequencing revealed that the fetus has carried compound heterozygous variants of the CPLANE1 gene, namely c.7978C>T and c.7169delT, which were respectively inherited from the husband and wife.
CONCLUSION
The c.7978C>T and c.7169delT compound heterozygous variants of the CPLANE1 gene probably underlay the dysplasia of cerebellar vermis in the fetus, which has provided a basis for genetic counseling and prenatal diagnosis.
Abnormalities, Multiple/genetics*
;
Cerebellum/diagnostic imaging*
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Eye Abnormalities/genetics*
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Female
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Fetus
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Humans
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Kidney Diseases, Cystic
;
Mutation
;
Phenotype
;
Pregnancy
;
Retina/abnormalities*
5.Report of a case with Joubert syndrome and literature review.
Ya-hui YI ; Gang LI ; Zhong-lie LU ; Jian-sheng ZHOU ; Zhen-wei YAO ; Peng-fei WANG ; Jin-xiang YAO
Chinese Journal of Pediatrics 2011;49(12):939-942
OBJECTIVETo explore the clinical feature, imaging and their diagnostic value for Joubert syndrome (JS).
METHODThe clinical data, imaging feature, and 31 references from China Biomedical literature database (CBMdise) were reviewed and analyzed.
RESULTThe age of onset of 32 patients including male 20 and female 12 ranged from 3 days to 6 years (mean 2.2 years). All the 32 patients with Joubert syndrome showed "slow growth" and "reduced muscle tension", 26 cases (81.3%) showed "gasp for breath", 26 cases (81.3%) showed "unusual motion of eyeball", 2 cases (6.3%) showed additional fingers (toes), 6 cases (18.8%) showed stretching tongue with agape. The typical imaging features of Joubert syndrome included "molar tooth sign", "midline cleavage" between cerebellar hemispheres and "bat-wing" like fourth ventricle, all the 32 patients with Joubert syndrome showed "midline cleavage", "molar tooth sign" was present in 29 cases (90.1%), and "bat-wing" like fourth ventricle in 30 cases (93.8%).
CONCLUSIONJoubert syndrome is a rare congenital brain malformation. The typical clinical manifestations included "gasp for breath", "reduced tension of muscle", "slow growth" and "unusual motion of eyeball", and at the same time the patients had the following typical imaging features of brain: "molar tooth sign", "midline cleavage" and "bat-wing" like fourth ventricle.
Abnormalities, Multiple ; Cerebellar Diseases ; diagnosis ; physiopathology ; Cerebellum ; abnormalities ; Child ; Eye Abnormalities ; diagnosis ; physiopathology ; Female ; Humans ; Kidney Diseases, Cystic ; diagnosis ; physiopathology ; Male ; Retina ; abnormalities ; physiopathology
6.Diagnosis of two cases from one family with Joubert syndrome caused by novel mutations of TCTN1 gene by whole exome sequencing.
Huanhuan WANG ; Wenting JIANG ; Mengyao DAI ; Bing XIAO ; Yan XU ; Yu SUN ; Yu LIU ; Xiaomin YING ; Yunlong SUN ; Wei WEI ; Xing JI
Chinese Journal of Medical Genetics 2019;36(7):686-689
OBJECTIVE:
To explore the pathogenesis of two fetuses from one family affected with Joubert syndrome (JS).
METHODS:
Whole exome sequencing was employed to screen potential mutations in both fetuses. Suspected mutations were verified by Sanger sequencing. Impact of intronic mutations on DNA transcription was validated by cDNA analysis.
RESULTS:
Two novel TCTN1 mutations, c.342-8A>G and c.1494+1G>A, were identified in exons 2 and 12, respectively.cDNA analysis confirmed the pathogenic nature of both mutations with interference of normal splicing resulting in production of truncated proteins.
CONCLUSION
The genetic etiology of the family affected with JS has been identified.Above findings have enriched the mutation spectrum of TCTN1gene and facilitated understanding of the genotype-phenotype correlation of JS.
Abnormalities, Multiple
;
diagnosis
;
genetics
;
Cerebellum
;
abnormalities
;
Eye Abnormalities
;
diagnosis
;
genetics
;
Humans
;
Kidney Diseases, Cystic
;
diagnosis
;
genetics
;
Membrane Proteins
;
genetics
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Mutation
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Pedigree
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Retina
;
abnormalities
;
Whole Exome Sequencing
7.Clinical features and genetic analysis of two Chinese pedigrees affected with Joubert syndrome.
Dengzhi ZHAO ; Yan CHU ; Ke YANG ; Xiaodong HUO ; Xingxing LEI ; Yanli YANG ; Chaoyang ZHANG ; Hai XIAO ; Shixiu LIAO
Chinese Journal of Medical Genetics 2023;40(1):21-25
OBJECTIVE:
To explore the clinical characteristics and genetic basis of two Chinese pedigrees affected with Joubert syndrome.
METHODS:
Clinical data of the two pedigrees was collected. Genomic DNA was extracted from peripheral blood samples and subjected to high-throughput sequencing. Candidate variants were verified by Sanger sequencing. Prenatal diagnosis was carried out for a high-risk fetus from pedigree 2.
RESULTS:
The proband of pedigree 1 was a fetus at 23+5 weeks gestation, for which both ultrasound and MRI showed "cerebellar vermis malformation" and "molar tooth sign". No apparent abnormality was noted in the fetus after elected abortion. The fetus was found to harbor c.812+3G>T and c.1828G>C compound heterozygous variants of the INPP5E gene, which have been associated with Joubert syndrome type 1. The proband from pedigree 2 had growth retardation, mental deficiency, peculiar facial features, low muscle tone and postaxial polydactyly of right foot. MRI also revealed "cerebellar dysplasia" and "molar tooth sign". The proband was found to harbor c.485C>G and c.1878+1G>A compound heterozygous variants of the ARMC9 gene, which have been associated with Joubert syndrome type 30. Prenatal diagnosis found that the fetus only carried the c.485C>G variant. A healthy infant was born, and no anomalies was found during the follow-up.
CONCLUSION
The compound heterozygous variants of the INPP5E and ARMC9 genes probably underlay the disease in the two pedigrees. Above finding has expanded the spectrum of pathogenic variants underlying Joubert syndrome and provided a basis for genetic counseling and prenatal diagnosis.
Female
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Humans
;
Pregnancy
;
Pedigree
;
Cerebellum/abnormalities*
;
Abnormalities, Multiple/diagnosis*
;
Eye Abnormalities/diagnosis*
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Kidney Diseases, Cystic/diagnosis*
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Phosphoric Monoester Hydrolases/genetics*
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Retina/abnormalities*
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East Asian People
;
Mutation
8.Clinical and genetic analyses of Joubert syndrome in children.
Guang-Yu ZHANG ; Yun-Xia ZHAO ; Hui-Ling ZHAO ; Guo-Hao TANG ; Peng-Liang WANG ; Deng-Na ZHU
Chinese Journal of Contemporary Pediatrics 2023;25(5):497-501
OBJECTIVES:
To study the clinical and genetic features of Joubert syndrome (JS) in children.
METHODS:
A retrospective analysis was performed on the clinical data, genetic data, and follow-up data of 20 children who were diagnosed with JS in the Department of Children's Rehabilitation, the Third Affiliated Hospital of Zhengzhou University, from January 2017 to July 2022.
RESULTS:
Among the 20 children with JS, there were 11 boys and 9 girls. The common clinical manifestations were developmental delay (20 children, 100%), abnormal eye movement (19 children, 95%), and hypotonia (16 children, 80%), followed by abnormal respiratory rhythm in 5 children (25%) and unusual facies (including prominent forehead, low-set ears, and triangular mouth) in 3 children (15%), and no limb deformity was observed. All 20 children (100%) had the typical "molar tooth sign" and "midline cleft syndrome" on head images, and 6 children (30%) had abnormal eye examination results. Genetic testing was performed on 7 children and revealed 6 pathogenic genes, i.e., the CPLANE1, RPGRIP1L, MKS1, CC2D2A, CEP120, and AHI1 genes.
CONCLUSIONS
For children with developmental delay, especially those with abnormal eye movement and hypotonia, it is recommended to perform a head imaging examination to determine the presence or absence of "molar tooth sign" and "midline cleft syndrome", so as to screen for JS to avoid missed diagnosis and misdiagnosis. There are many pathogenic genes for JS, and whole-exome sequencing can assist in the diagnosis of JS.
Male
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Female
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Humans
;
Child
;
Cerebellum
;
Abnormalities, Multiple/genetics*
;
Kidney Diseases, Cystic/genetics*
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Eye Abnormalities/genetics*
;
Retina
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Retrospective Studies
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Muscle Hypotonia/genetics*
9.Clinical and genetic analysis for a Joubert syndrome family with CC2D2A gene mutations.
Yanhua SU ; Jiansheng XIE ; Shanshan YU ; Hongyu LUO ; Weiqing WU ; Zhiyong XU
Chinese Journal of Pediatrics 2015;53(6):431-435
OBJECTIVETo confirm the genetic diagnosis for providing services for genetic counseling and prenatal diagnosis, we analyzed the clinical and genetic data of a pedigree which is clinically diagnosed as Joubert syndrome.
METHODA Joubert syndrome pedigree was enrolled as subject of this study from our hospital's outpatients in 2013. Following the medical history collection of the proband and the suffering fetus, target sequence capture and the next-generation sequencing technology were used for the proband and the suffering fetus to find the causative genes and sanger sequencing for the members of the pedigree to check and verify if the inherited mutations are in accordance with the Mendelian inheritance. Combining the clinical symptoms and signs with the total testing results, we analyzed the Joubert syndrome pedigree clinically and genetically.
RESULTThe proband showed abnormal respiratory patterns (neonatal tachypnea) and hypertonia without abnormal eye movements, and reflected the molar tooth sign on the magnetic resonance imaging. And afterwards the patient developed hypotonia, ataxia, growth and intellectual disability accompanied by congenital blepharoptosis. There were no any symptoms and signs of liver, kidney and eyesight abnormalities so far. The affected fetus showed hydrocephalus by the auxiliary examination during the second trimesters of pregnancy without any appearance deformities. Both the proband and the affected fetus carried a missense mutation of CC2D2A gene c.2999A > T (p.Glu1000Val) from their father and carried the deletion of exon 20-21 on the same gene. Both variations were confirmed to be the Mendelian genetic compound heterozygous pattern. Whereas, the missense mutations c.2999A > T (p.Glu1000Val) on the CC2D2A gene have been proved to be inherited from the proband's father and the proband as well as the affected fetus. However, the proband's mother was normal at this locus of CC2D2A gene. The missense mutations c.2999A >T (p.Glu1000Val) have been confirmed to accord with Mendelian inheritance.
CONCLUSIONThe Joubert syndrome patient may show hypertonia in the early postnatal days as a result of hydrocephalus during the second and third trimesters of pregnancy besides manifesting hypotonia, ataxia, growth and intellectual disability markedly with age accompanied by the congenital blepharoptosis and revealing the molar tooth sign on the magnetic resonance imaging, considering the medical history and the whole testing results, the compound heterozygous mutations of c.2999A > T (p.Glu1000Val) and deletion of exon 20-21 of CC2D2A gene in the pedigree may be the causal gene mutations.
Abnormalities, Multiple ; genetics ; Cerebellar Diseases ; Cerebellum ; abnormalities ; Exons ; Eye Abnormalities ; genetics ; Female ; Genetic Testing ; Heterozygote ; Humans ; Hydrocephalus ; Kidney Diseases, Cystic ; genetics ; Male ; Mutation ; Pedigree ; Pregnancy ; Prenatal Diagnosis ; Proteins ; genetics ; Retina ; abnormalities
10.Genetic testing and prenatal diagnosis for two families affected with Joubert syndrome.
Zhouxian BAI ; Shuang HU ; Ning LIU ; Qinghua WU ; Xiangdong KONG
Chinese Journal of Medical Genetics 2020;37(5):509-513
OBJECTIVE:
To identify pathogenic variants in two families with patients suspected for Joubert syndrome(UBST) by cerebellar vermis hypoplasia.
METHODS:
Clinical data and peripheral venous blood and skin tissue samples were collected for the extraction of genomic DNA. Potential variants were screened by using targeted capture and next generation sequencing. Suspected variants were validated by PCR and Sanger sequencing. The frequency of the variants in the population was calculated. Pathogenicity of the variants was predicted by following the guidelines of the American College of Medical Genetics and Genomics (ACMG). Prenatal diagnosis was provided to these families upon subsequent pregnancy.
RESULTS:
The proband of family 1 was found to harbor homozygous c.2072delT (p.F691S*fs19) frameshift variant of the AHI1 gene, which may cause premature termination of translation of the Abelson helper integration site 1 after the 691st amino acid. The proband of family 2 was found to harbor compound heterozygous variants of the CPLANE1 gene, namely c.7243dupA (p.T2415Nfs*7) and c.8001delG (p.K2667Nfs*31), which can respectively lead to premature termination of translation of ciliogenesis and planar polarity effector 1 after the 2145th and 2667th amino acids. All of the three variants were previously unreported, and were predicted to be pathogenic by bioinformatic analysis.
CONCLUSION
The AHI1 c.2072delT and CPLANE1 c.7243dupA and c.8001delG variants probably underlay JBTS3 in family 1 and JBTS17 in family 2, respectively. Based on above results, prenatal diagnosis may be offered to the affected families upon their subsequent pregnancies.
Abnormalities, Multiple
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diagnosis
;
genetics
;
Adaptor Proteins, Vesicular Transport
;
genetics
;
Cerebellum
;
abnormalities
;
Eye Abnormalities
;
diagnosis
;
genetics
;
Female
;
Genetic Testing
;
Genetic Variation
;
Humans
;
Kidney Diseases, Cystic
;
diagnosis
;
genetics
;
Membrane Proteins
;
genetics
;
Mutation
;
Pregnancy
;
Prenatal Diagnosis
;
Retina
;
abnormalities