A mutated CRYGD associated with congenital coralliform cataracts in two Chinese pedigrees

AIM: To investigate the causal gene mutation and clinical characteristics for two Chinese families with autosomal dominant congenital coralliform cataract. METHODS: Two Chinese pedigrees with congenital cataract were investigated. Routine ophthalmic examinations were performed on all patients and non-affected family members. Peripheral blood samples were collected, and the genomic DNAs were extracted. The coding regions of proband’s DNAs were analyzed with cataract gene panel. The identified mutation was amplified by polymerase chain reaction, and automated sequencing was performed in other members of two families to verify whether the mutated gene was co-segregated with the disease. RESULTS: Congenital coralliform cataract was inherited in an autosomal dominant mode in both pedigrees. For each family, more than half of the family members were affected. All patients presented with severe visual impairment after birth as a result of bilateral symmetric coralliform lens opacification. An exact the same defect in the same gene, a heterozygous mutation of c.70C>A (p. P24T) in exon 2 of γD-crystallin gene, was detected in both probands from each family. Sanger sequencing analysis demonstrated that the mutated CRYGD was co-segregated in these two families. CONCLUSION: A c.70C>A (p. P24T) variant in CRYGD gene was reconfirmed to be the causal gene in two Chinese pedigrees. It is known that mutated CRYGD caused most of the congenital coralliform cataracts, suggesting that the CRYGD gene is associated with coralliform congenital cataract.

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A Novel CRYBB2 Stopgain Mutation Causing Congenital Autosomal Dominant Cataract in a Chinese Family

Journal of Ophthalmology ◽

10.1155/2016/4353957 ◽

2016 ◽

Vol 2016 ◽

pp. 1-8 ◽

Cited By ~ 2

Author(s):

Yu Zhou ◽

Yaru Zhai ◽

Lulin Huang ◽

Bo Gong ◽

Jie Li ◽

...

Keyword(s):

Exome Sequencing ◽

Whole Exome Sequencing ◽

Congenital Cataract ◽

Autosomal Dominant ◽

Family Members ◽

Chinese Family ◽

Heterozygous Mutation ◽

Whole Exome ◽

Causal Mutation ◽

Control Samples

Congenital cataract is the most common cause of the visual disability and blindness in childhood. This study aimed to identify gene mutations responsible for autosomal dominant congenital cataract (ADCC) in a Chinese family using next-generation sequencing technology. This family included eight unaffected and five affected individuals. After complete ophthalmic examinations, the blood samples of the proband and two available family members were collected. Then the whole exome sequencing was performed on the proband and Sanger sequencing was applied to validate the causal mutation in the two family members and control samples. After the whole exome sequencing data were filtered through a series of existing variation databases, a heterozygous mutation c.499T<G (p.E167X) in CRYBB2 gene was found. And the results showed that the mutation cosegregated with the disease phenotype in the family and was absolutely absent in 1000 ethnicity-matched control samples. Thus, the heterozygous mutation c.499T<G (p.E167X) in CRYBB2 was the causal mutation responsible for this ADCC family. In conclusion, our findings revealed a novel stopgain mutation c.499T<G (p.E167X) in the exon 6 of CRYBB2 which expanded the mutation spectrum of CRYBB2 in Chinese congenital cataract population and illustrated the important role of CRYBB2 in the genetics research of congenital cataract.

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A novel missense mutation of GJA8 causes congenital cataract in a large Mauritanian family

European Journal of Ophthalmology ◽

10.1177/1120672118804757 ◽

2018 ◽

Vol 29 (6) ◽

pp. 621-628 ◽

Cited By ~ 1

Author(s):

Mouna Hadrami ◽

Crystel Bonnet ◽

Fatimetou Veten ◽

Christina Zeitz ◽

Christel Condroyer ◽

...

Keyword(s):

Congenital Cataract ◽

Autosomal Dominant ◽

Family Members ◽

Dominant Mode ◽

Wild Type ◽

New Mutation ◽

The Family ◽

History Of ◽

Eye Examination ◽

Generation Sequencing

Objective of the study: Inborn lens opacity is the most frequent cause of childhood blindness. In this study, we aimed to define the presumed genetic cause of a congenital cataract present in a Mauritanian family over the last nine generations. Methods: A family history of the disease and eye examination were carried out for the family members. Next-generation sequencing using a panel of 116 cataract underlying genes was selectively conducted on the proband’s DNA. Nucleotide and amino acid changes and their impact on the phenotype were evaluated using various data analyzing software. Results: Congenital nuclear cataract, with autosomal dominant mode, was observed in the family. All patients had consequences on their vision in the first 2 years of life. Genetic screening revealed a new mutation c.166A>C (p.Thr56Pro) in GJA8, encoding the Cx50 α-connexin protein. This mutation co-segregated in all patients and was not observed in the unaffected family members and controls. The predicted secondary structure impacted by p.Thr56Pro revealed a localized disruption, in the first extra membrane loop of the wild-type sheet, which is replaced in the mutant protein by a turn then a coil. This conformational change was functionally predicted as probably damaging. Conclusion: A new mutation (c.166A>C) in GJA8 underlying a nuclear congenital cataract was identified in this study. Its segregation with the phenotype might be useful as a predicting marker of the disease.

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Molecular Diagnosis of One Pedigree with Protein S Deficiency and Antithrombin Deficiency

Blood ◽

10.1182/blood.v120.21.5140.5140 ◽

2012 ◽

Vol 120 (21) ◽

pp. 5140-5140

Author(s):

Rong-Fu Zhou ◽

Hong Tao ◽

Jian Ouyang ◽

Xian Zhang ◽

Yonggong Yang ◽

...

Keyword(s):

Conflicts Of Interest ◽

Novel Mutation ◽

Color Doppler ◽

Femoral Vein ◽

Family Members ◽

Protein S ◽

Heterozygous Mutation ◽

Sequencing Analysis ◽

Antithrombin Deficiency ◽

Exon 4

Abstract Abstract 5140 Objective To identify gene mutations for one patient and his family members with protein S and antithrombin deficiency. Methods ELISA were used to detect protein S (PS), protein C (PC) and antithrombin (AT) activities for the proband and family members, respectively. The genomic DNA was extracted from the peripheral blood of proband and family members. All exons and their flanks of protein S gene and antithrombin gene were amplified by polymerase chain reaction (PCR). The PCR products were sequenced directly. The mutation-related exons of his famliy members were amplified by PCR and sequenced directly. Results The proband was a 49-year-old male. He presented with sudden left lower extremity swelling and pain without casues. Regular examination revealed that his APTT, PT, and TT were all in normal levels, but D- dimmer was 5. 62mg/L, Color doppler ultrasonography showed thrombosis in his left femoral vein. The activity of PS for his family members was ‡1 0%, ‡2 0%, ‡3 0%, ‡4 130. 8%, ‡5 8. 4%, ‡1 0%, ‡2 0%, and that of AT was ‡1 129. 1%, ‡2 51. 9%, ‡3 73.2%, ‡4 119. 1%, ‡5 136. 2%, ‡1 65. 5% and ‡2 60. 1%, respectively. The sequencing analysis showed that a heterozygous missense mutation G68395T (NG_009813. 1) was detected in Exon 4 of PS gene leading to the substitution of Arg90 by Leu (NP_000304. 2) for the propositus. The heterozygous mutation (Arg90Leu) was also found in other family members. A heterozygous (nonsense) mutation G12444A (NG_012462. 1) was detected in Exon 4 of AT gene leading to Trp257Ter (NP_000479. 1) for the propositus. The mutation (Trp257Ter) was found in other family members with reduced activity of AT. These two mutations (G68395T in PS gene and G12444A in AT gene) were not reported before and were thus novel ones. Conclusion The novel mutation G68395T in PS gene and G12444A in AT gene might be the causes of deficiency of PS and AT for the family. Disclosures: No relevant conflicts of interest to declare.

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Familial Phonological Disorders

Journal of Speech and Hearing Disorders ◽

10.1044/jshd.5501.160 ◽

1990 ◽

Vol 55 (1) ◽

pp. 160-170 ◽

Cited By ~ 27

Author(s):

Barbara A. Lewis

Keyword(s):

Learning Disabilities ◽

Autosomal Dominant ◽

Threshold Model ◽

Family Members ◽

Speech Disorders ◽

Dominant Mode ◽

Incomplete Penetrance ◽

Phonological Disorders ◽

Language Problems ◽

Mode A

The pedigrees of 4 children with a severe phonological disorder demonstrating three generations of members with speech/language problems are presented. All 4 probands were female with two mothers, two fathers, and five out of six siblings affected. All pedigrees contained family members with dyslexia and learning disabilities as well as speech disorders. Family members varied in the type of speech problems that they demonstrated and the severity of their disorder, thus suggesting variable expressivity and incomplete penetrance. An autosomal dominant mode, a multifactorial-polygenic model, and a sex-specific threshold model for expression are discussed.

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Autosomal dominant neurohypophyseal diabetes insipidus in a Swiss family, caused by a novel mutation (C59Delta/A60W) in the neurophysin moiety of prepro-vasopressin-neurophysin II (AVP-NP II)

Acta Endocrinologica ◽

10.1530/eje.0.1450439 ◽

2001 ◽

pp. 439-444 ◽

Cited By ~ 17

Author(s):

CE Fluck ◽

J Deladoey ◽

S Nayak ◽

O Zeller ◽

P Kopp ◽

...

Keyword(s):

Diabetes Insipidus ◽

Water Deprivation ◽

Autosomal Dominant ◽

Amino Acid Level ◽

Family Members ◽

Magnetic Resonance Images ◽

Bright Spot ◽

Molecular Characteristics ◽

Exon 2 ◽

Water Deprivation Test

OBJECTIVE: To study clinical, morphological and molecular characteristics in a Swiss family with autosomal dominant familial neurohypophyseal diabetes insipidus (adFNDI). PARTICIPANTS AND METHODS: A 15-month-old girl presenting with symptoms of polydipsia and polyuria was investigated by water deprivation test. Evaluation of the family revealed three further family members with symptomatic vasopressin-deficient diabetes insipidus. T1-weighted magnetic resonance images of the posterior pituitary were taken in two affected adult family members and molecular genetic analysis was performed in all affected individuals. RESULTS: The water deprivation test in the 15-month-old child confirmed the diagnosis of vasopressin-deficient diabetes insipidus and the pedigree was consistent with autosomal dominant inheritance. The characteristic bright spot of the normal vasopressin-containing neurophypophysis was absent in both adults with adFNDI. Direct sequence analysis revealed a new deletion (177-179DeltaCGC) in exon 2 of the AVP-NP II gene in all affected individuals. At the amino acid level, this deletion eliminates cysteine 59 (C59Delta) and substitutes alanine 60 by tryptophan (A60W) in the AVP-NP II precursor; interestingly, the remainder of the reading frame remains unchanged. According to the three-dimensional structure of neurophysin, C59 is involved in a disulphide bond with C65. CONCLUSIONS: Deletion of C59 and substitution of A60W in the AVP-NP II precursor is predicted to disrupt one of the seven disulphide bridges required for correct folding of the neurophysin moiety and thus disturb the function of neurophysin as the vasopressin transport protein. These data are in line with the clinical and morphological findings in the reported family with adFNDI.

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Novel SOX2 Mutation in Autosomal Dominant Cataract-Microcornea Syndrome

10.21203/rs.3.rs-1085640/v1 ◽

2021 ◽

Author(s):

Zhi-Bo Lin ◽

Jin Li ◽

Hai-Sen Sun ◽

A-Yong Yu ◽

Shi-Hao Chen ◽

...

Keyword(s):

Exome Sequencing ◽

Missense Mutation ◽

Whole Exome Sequencing ◽

Sanger Sequencing ◽

Congenital Cataract ◽

Autosomal Dominant ◽

Family Members ◽

High Mobility ◽

Chinese Family ◽

Whole Exome

Abstract Background: Congenital cataract-microcornea syndrome (CCMC) is characterized by the association of congenital cataract and microcornea without any other systemic anomaly or dysmorphism. Although several causative genes have been reported in patients with CCMC, the genetic etiology of CCMC is yet to be clearly understood. Purpose: To unravel the genetic cause of autosomal dominant family with CCMC.Methods: All patients and available family members underwent a comprehensive ophthalmologic clinical examination in the hospital by expert ophthalmologists and carried out to clinically diagnosis. All the patients were screened by whole-exome sequencing and then validated using co-segregation by Sanger sequencing. Results: Four CCMC patients from a Chinese family, and five unaffected family members were enrolled in this study. Using whole-exome sequencing, missense mutation c.295G>T (p.a99s, NM_003106.4) in the SOX2 gene was identified and validated by segregation analysis. In addition, this missense mutation was predicted to be damaging by multiple predictive tools. Variant p.Ala99Ser was located in a conservation high mobility group (HMG)-box domain in SOX2 protein, with a potential pathogenic impact of p.Ala99Ser on protein level.Conclusions: A novel missense mutation (c.295G>T, p.Ala99Ser) in the SOX2 gene was found in this Han Chinese family with congenital cataract and microcornea. Our study firstly determined that mutations in SOX2 were associated with CCMC, warranting further investigations on the pathogenesis of this disorder. This result expands the mutation spectrum of SOX2 and provides useful information to study the molecular pathogenesis of CCMC.

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Two Novel Mutations of the Vasopressin Gene Associated with Familial Diabetes Insipidus and Identification of an Asymptomatic Carrier Infant1

The Journal of Clinical Endocrinology & Metabolism ◽

10.1210/jcem.83.11.5278 ◽

1998 ◽

Vol 83 (11) ◽

pp. 3958-3964

Author(s):

Frederick D. Grant ◽

Arshanoush Ahmadi ◽

Catherine M. Hosley ◽

Joseph A. Majzoub

Keyword(s):

Diabetes Insipidus ◽

Genomic Dna ◽

Autosomal Dominant ◽

Restriction Site ◽

Asymptomatic Carrier ◽

Dominant Mode ◽

Heterozygous Mutation ◽

Novel Mutations ◽

Balance Study ◽

Vasopressin Gene

Familial diabetes insipidus (FDI) is a syndrome of central vasopressin deficiency that is inherited in an autosomal dominant manner and that typically becomes clinically apparent in the first decade of life. Two novel mutations of the vasopressin gene have been identified in two previously unstudied kindreds with FDI. In each kindred, the inheritance of the FDI phenotype was consistent with an autosomal dominant mode of inheritance. In each proband, the diagnosis of central diabetes insipidus had been confirmed previously with a water deprivation protocol. After extraction of genomic DNA from each individual, the three exons of the vasopressin gene were separately amplified by PCR and directly sequenced using an automated dye termination method. In the proband and two other carriers of one kindred, a heterozygous C to T mutation was identified at nucleotide 1857. This is predicted to produce a serine to phenylalanine substitution at residue 56 of the vasopressin-related neurophysin peptide encoded by the mutated allele. The mutation also abolished an MspI site in the vasopressin sequence, and analysis of genomic DNA from eight members of the kindred (five with FDI) confirmed segregation of the mutation with the FDI phenotype. Another member of the kindred, a 13-month-old infant, also has the heterozygous C to T mutation, but a formal water balance study showed no evidence of diabetes insipidus. In the proband of the other kindred, a heterozygous G to A mutation was identified at nucleotide 1873. This mutation would be predicted to cause a cysteine to tyrosine substitution at residue 61 of the neurophysin encoded by the mutated allele. This heterozygous mutation was confirmed by the presence of an RsaI restriction site in one vasopressin allele in two members of the kindred. Therefore, two novel heterozygous mutations of the vasopressin gene have been identified in FDI kindreds. In one kindred, an asymptomatic carrier infant was identified and will require continued observation to determine whether she will develop clinical diabetes insipidus. The presence of these two novel mutations in a region of the vasopressin gene where other FDI mutations have been reported suggests that the part of the neurophysin peptide encoded by these sequences may be critically important in the appropriate expression of vasopressin.

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Abstract 198: Familial Hypercholesterolemia and Intra-Cranial Aneurysm: A Novel Phenotypic and Genetic Association

Arteriosclerosis Thrombosis and Vascular Biology ◽

10.1161/atvb.35.suppl_1.198 ◽

2015 ◽

Vol 35 (suppl_1) ◽

Author(s):

Arvind K Pandey ◽

Jason R Becker

Keyword(s):

Familial Hypercholesterolemia ◽

Intracranial Aneurysms ◽

Autosomal Dominant ◽

Vascular Malformations ◽

Low Density Lipoprotein ◽

Family Members ◽

Density Lipoprotein ◽

Pedigree Analysis ◽

Dominant Mode ◽

Illumina Hiseq

Background: Autosomal dominant familial hypercholesterolemia (FH) is characterized by elevated levels of low density lipoprotein (LDL) cholesterol. Mutations in LDLR, APOB, and PCSK9 genes are established causes of this condition. However, in up to 20-40% of cases, the genetic cause has not been defined. FH is associated with coronary ectasias, but extra-cardiac vascular malformations have not been described. Methods: A subject with hypercholesterolemia was evaluated, and a three generation pedigree was constructed. Whole exome sequencing (WES) was performed (Illumina HiSeq 2500, 100x avg coverage) and reads were aligned to a human reference genome (hg19) using BWA. Variants were called with GATK Unified Genotyper and annotated using SeattleSeq. Results: Pedigree analysis suggested an autosomal dominant mode of inheritance of the hypercholesterolemia trait (Fig 1). Multiple family members also had intracranial aneurysms. Targeted analysis of the classical genes associated with FH (LDLR, APOB, and PCSK9) did not identify any missense, nonsense, or splice site variants with a minor allele frequency (MAF) < 0.01. Expanded analysis of the entire exome yielded rare missense variants (MAF < 0.001) in 845 genes and nonsense variants in 22 genes. Conclusions: Utilizing WES we rapidly screened an individual for pathogenic DNA variants in genes previously associated with FH. The genetic factor underlying our patient’s FH appears to be distinct from the known causes of FH. Genetic analysis of additional family members will be necessary to define the novel genetic cause of FH in this pedigree and explore the relationship of intracranial aneurysms with FH.

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A novel missense mutation of CRYBB1 causes congenital cataract in a Chinese family

European Journal of Ophthalmology ◽

10.1177/1120672120914497 ◽

2020 ◽

pp. 112067212091449

Author(s):

Yanan Ji ◽

Xiangyu Zhao ◽

Juanmei Zhang ◽

Dan Zhang ◽

Chunliu Tian ◽

...

Keyword(s):

Missense Mutation ◽

Protein Function ◽

Congenital Cataract ◽

Family Members ◽

Causative Mutation ◽

Chinese Family ◽

Heterozygous Mutation ◽

Nuclear Cataract ◽

Mutation Site ◽

The Family

Objective of the study: To identify the pathogenic gene and mutation site of a Chinese family with congenital cataract. Methods: Eight family members and 100 controls were employed, and targeted exome sequencing was used to identify the genetically pathogenic factor of the proband. Results: Targeted next-generation sequencing identified a novel missense mutation c.209A>C (p.Q70P) of CRYBB1 gene in the family. Sanger sequencing results showed that this heterozygous mutation was a causative mutation, which was not found in unaffected family members and healthy controls. Bioinformatics predicts that the effect of this mutation on protein function is probably harmful. Conclusion: We demonstrate that c.209A>C of CRYBB1 gene is a pathogenic mutation in the family of congenital nuclear cataract in this study. This is the first report that this mutation leads to congenital nuclear cataract, which broadens the mutation spectrum of CRYBB1 gene in congenital nuclear cataract.

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Congenital Hypogonadotropic Hypogonadism with Anosmia and Gorlin Features Caused by a PTCH1 Mutation Reveals a New Candidate Gene for Kallmann Syndrome

Neuroendocrinology ◽

10.1159/000506640 ◽

2020 ◽

Vol 111 (1-2) ◽

pp. 99-114 ◽

Cited By ~ 3

Author(s):

Sara Barraud ◽

Brigitte Delemer ◽

Céline Poirsier-Violle ◽

Jérôme Bouligand ◽

Jean-Claude Mérol ◽

...

Keyword(s):

Candidate Gene ◽

Messenger Rna ◽

Novel Mutation ◽

Hypogonadotropic Hypogonadism ◽

Family Members ◽

Clinical Signs ◽

Dominant Mode ◽

Kallmann Syndrome ◽

Heterozygous Mutation ◽

Congenital Hypogonadotropic Hypogonadism

Background: Two loci (CHD7 and SOX10) underlying Kallmann syndrome (KS) were discovered through clinical and genetic analysis of CHARGE and Waardenburg syndromes, conditions that include congenital anosmia caused by olfactory bulb (CA/OBs) defects and congenital hypogonadotropic hypogonadism (CHH). We hypothesized that other candidate genes for KS could be discovered by analyzing rare syndromes presenting with these signs. Study Design, Size, Duration: We first investigated a family with Gorlin-Goltz syndrome (GGS) in which affected members exhibited clinical signs suggesting KS. Participants/Materials, Methods: Proband and family members underwent detailed clinical assessment. The proband received detailed neuroendocrine evaluation. Genetic analyses included sequencing the PTCH1 gene at diagnosis, followed by exome analyses of causative or candidate KS/CHH genes, in order to exclude contribution to the phenotypes of additional mutations. Exome analyses in additional 124 patients with KS/CHH probands with no additional GGS signs. Results: The proband exhibited CA, absent OBs on magnetic resonance imaging, and had CHH with unilateral cryptorchidism, consistent with KS. Pulsatile Gonadotropin-releasing hormone (GnRH) therapy normalized serum gonadotropins and increased testosterone levels, supporting GnRH deficiency. Genetic studies revealed 3 affected family members harbor a novel mutation of PTCH1 (c.838G> T; p.Glu280*). This unreported nonsense deleterious mutation results in either a putative truncated Ptch1 protein or in an absence of translated Ptch1 protein related to nonsense mediated messenger RNA decay. This heterozygous mutation cosegregates in the pedigree with GGS and CA with OBs aplasia/hypoplasia and with CHH in the proband suggesting a genetic linkage and an autosomal dominant mode of inheritance. No pathogenic rare variants in other KS/CHH genes cosegregated with these phenotypes. In additional 124 KS/CHH patients, 3 additional heterozygous, rare missense variants were found and predicted in silico to be damaging: p.Ser1203Arg, p.Arg1192Ser, and p.Ile108Met. Conclusion: This family suggests that the 2 main signs of KS can be included in GGS associated with PTCH1 mutations. Our data combined with mice models suggest that PTCH1 could be a novel candidate gene for KS/CHH and reinforce the role of the Hedgehog signaling pathway in pathophysiology of KS and GnRH neuron migration.

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