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 ; Humans ; Pregnancy ; Pedigree ; Cerebellum/abnormalities* ; Abnormalities, Multiple/diagnosis* ; Eye Abnormalities/diagnosis* ; Kidney Diseases, Cystic/diagnosis* ; Phosphoric Monoester Hydrolases/genetics* ; Retina/abnormalities* ; East Asian People ; Mutation

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 ; 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

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 ; Mutation ; Pedigree ; Retina ; abnormalities ; Whole Exome Sequencing

OBJECTIVE: To determine the origin of supernumerary small marker chromosomes (sSMCs) carried by two fetuses. METHODS: Single nucleotide polymorphism array (SNP-array) and fluorescence in situ hybridization (FISH) analysis were carried out on cells cultured from the amniotic fluid samples. RESULTS: SNP-array analysis showed both fetuses to be arr[hg19]22q11.1q11.21(16 888 899-18 649 190)×4, with a duplicated 1.7 Mb region (16 888 899-18 649 190) leading to partial tetrasomy of 22q11.1-22q11.21. FISH confirmed that both fetuses were 47,XN,+mar.ish idic(22)(q11.2) (RP11-958H20 ++),which suggested a diagnosis of Cat-eye syndrome (CES). The appearance of abortuses were consistent with the diagnosis of CES. CONCLUSION Two fetuses with CES were diagnosed by genetic testing. The latter has provided a basis for genetic counseling.
Aneuploidy ; Chromosome Disorders ; diagnosis ; Chromosomes, Human, Pair 22 ; Eye Abnormalities ; diagnosis ; Female ; Fetus ; Humans ; In Situ Hybridization, Fluorescence ; Karyotyping ; Pregnancy ; Prenatal Diagnosis

Infant hemangioma, the most common benign tumor in children, is characterized by rapid proliferation, followed by slower spontaneous involution. However, some patients with facial segmental hemangioma are associated with PHACE syndrome. PHACE syndrome is characterized by vascular nerve and vascular cutaneous lesions of multiple systemic systems, often resulting in structural and functional impairments. Recent studies have demonstrated that the possible pathogeneses of PHACE syndrome mainly include hypoxia, abnormality of mesodermal vascular endothelial cells, genetic abnormality, and abnormality of interstitial mesenchymal stem cells. The current medications for hemangioma with PHACE syndrome include beta blockers, glucocorticoids, and mTOR inhibitors. This review article mainly describes the pathogenesis, diagnoses and treatments of PHACE syndrome, in order to provide directions for diagnosis and treatment of this disorder.
Abnormalities, Multiple ; diagnosis ; etiology ; therapy ; Eye Abnormalities ; diagnosis ; etiology ; therapy ; Heart Defects, Congenital ; diagnosis ; etiology ; therapy ; Hemangioma ; diagnosis ; etiology ; therapy ; Humans ; Infant

PURPOSE: To describe clinical findings in a Korean family with Axenfeld-Rieger syndrome. METHODS: A retrospective review of clinical data about patients with diagnosed Axenfeld-Rieger syndrome. Five affected members of the family underwent a complete ophthalmologic examination. We screened the forkhead box C1 gene and the pituitary homeobox 2 gene in patients. Peripheral blood leukocytes and buccal mucosal epithelial cells were obtained from seven members of a family with Axenfeld-Rieger syndrome. DNA was extracted and amplified by polymerase chain reaction, followed by direct sequencing. RESULTS: The affected members showed iris hypoplasia, iridocorneal adhesions, posterior embryotoxon, and advanced glaucoma in three generation. None had systemic anomalies. Two mutations including c.1362_1364insCGG and c.1142_1144insGGC were identified in forkhead box C1 in four affected family members. CONCLUSIONS: This study may help to understand clinical findings and prognosis for patients with Axenfeld-Rieger syndrome.
Aged, 80 and over ; Anterior Eye Segment/*abnormalities/metabolism ; DNA/*genetics ; DNA Mutational Analysis ; Eye Abnormalities/diagnosis/*genetics/metabolism ; Female ; Forkhead Transcription Factors/*genetics/metabolism ; Genetic Testing ; Homeodomain Proteins/*genetics/metabolism ; Humans ; Male ; Middle Aged ; *Mutation ; Pedigree ; Retrospective Studies ; Transcription Factors/*genetics/metabolism ; Young Adult

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

Townes-Brocks syndrome (TBS) is a rare genetic disorder characterized by the classic triad of congenital anomalies of the anus, thumbs, and ears, with variable expressivity. Additionally, renal malformations, cardiac anomalies, and endocrine and eye abnormalities can accompany TBS, although less frequently. TBS is inherited in an autosomal dominant fashion; however, about 50% of patients have a family history of TBS and the remaining 50% have de novo mutations. SALL1, located on chromosome 16q12.1, is the only causative gene of TBS. SALL1 acts as a transcription factor and may play an important role in inducing the anomalies during embryogenesis. Clinical features of TBS overlap with those of other multiple anomaly syndromes, such as VACTERL syndrome, Baller-Gerold syndrome, Goldenhar syndrome, cat eye syndrome, and Holt-Oram syndrome. Consequently, there are some difficulties in differential diagnosis based on clinical manifestations. Herein, we report a Korean family with two generations of TBS that was diagnosed based on physical examination findings and medical history. Although the same mutation in SALL1 was identified in both the mother and the son, they displayed different clinical manifestations, suggesting a phenotypic diversity of TBS.
Anal Canal ; Animals ; Anus, Imperforate ; Cats ; Diagnosis, Differential ; Ear ; Embryonic Development ; Eye Abnormalities ; Family Characteristics ; Female ; Goldenhar Syndrome ; Hearing Loss, Sensorineural ; Humans ; Mothers ; Physical Examination ; Polydactyly ; Pregnancy ; Thumb ; Transcription Factors

No abstract available.
Child ; Cornea/*abnormalities ; Cysts/*diagnosis ; Eye Abnormalities/*diagnosis ; Eye Diseases/*diagnosis ; Female ; Humans ; Visual Acuity/physiology ; Vitreous Body/*pathology

PURPOSE: To describe the clinical course of congenital aniridia and to evaluate prognostic factors for visual outcome after long-term follow-up. METHODS: The medical records of 120 eyes from 60 patients with congenital aniridia were retrospectively reviewed. The prevalence and clinical course of ophthalmic characteristics, systemic disease, refractive errors, and visual acuity were assessed. Prognostic factors for final visual outcomes were analyzed. RESULTS: Aniridic keratopathy developed in 82 (69%) of 119 eyes. Macular hypoplasia was observed in 70 eyes of 35 patients (91%). Cataract was observed in 63 of 120 eyes (53%). Nystagmus was present in 41 patients (68% of 60 patients) at the initial visit but decreased in five patients (8% of 60 patients). Ocular hypertension was detected in 19 eyes (20% of 93 eyes), six (32% of 19 eyes) of which developed secondarily after cataract surgery. The mean changes in spherical equivalent and astigmatism during the follow-up period were -1.10 and 1.53 diopter, respectively. The mean final visual acuity was 1.028 logarithm of minimal angle of resolution. Nystagmus and ocular hypertension were identified as prognostic factors for poor visual outcome. CONCLUSIONS: Identification of nystagmus and ocular hypertension was important to predict final visual outcome. Based on the high rate of secondary ocular hypertension after cataract surgery, careful management is needed.
Adolescent ; Adult ; Aniridia/*diagnosis/physiopathology ; Cataract/diagnosis ; Child ; Child, Preschool ; Corneal Diseases/diagnosis ; Eye Abnormalities/diagnosis ; Eye Diseases/*diagnosis/physiopathology ; Follow-Up Studies ; Humans ; Infant ; Infant, Newborn ; Nystagmus, Pathologic/diagnosis ; Ocular Hypertension/diagnosis ; Prognosis ; Retina/abnormalities ; Retrospective Studies ; Visual Acuity/*physiology ; Young Adult