A novel mutation in PAX6 gene causing congenital iris coloboma with congenital cataract in a pedigree / 中华实验眼科杂志

Objective:To identify the pathogenic gene and inheritance pattern in a pedigree of congenital iris coloboma with congenital cataract.Methods:The method of pedigree investigation was adopted.A pedigree of congenital iris coloboma with congenital cataract was collected by Yunnan Disabled Rehabilitation Center and the 2nd Afliated Hospital of Kunming Medical University in February 2020.Ophthalmic examinations were carried out on the female proband, her parents, her children and her husband, and the clinical diagnosis was made.Genomic DNA was extracted from peripheral blood samples collected from the family members.The suspected pathogenic gene in the proband and her husband was screened by whole exome sequencing and was identified by bioinformatics analysis.The amino acid conservation was analyzed by UGENE software.The impact of the mutation on protein translation was predicted using MutationTaster software.The pathogenicity of the mutation was assessed according to the American College of Medical Genetics (ACMG) Standards and Guidelines.Pathogenic gene and mutations were verified by Sanger sequencing.This study adhered to the Declaration of Helsinki.The study protocol was approved by the Ethics Committee of the 2nd Afliated Hospital of Kunming Medical University (No.PJ-2020-61).Written informed consent was obtained from each subject or custodian.Results:The proband showed large iris defects in both eyes with only a small amount of observable iris tissue in the periphery, lens cortical opacity and posterior capsule opacification, accompanied by nystagmus.A novel heterozygous frameshift variation c. 415dupA (p.R139fs) was located in exon 8 of PAX6 gene, and the variation was conservative across multiple species.The variation was in the highly conserved region of PAX6 gene and caused the dysfunction of PAX6 protein.The variation was graded as PVS1+ PM2+ PP1, a pathogenic variation, based on ACMG guidelines.The pedigree was consistent with co-segregation, indicating that the novel variation was pathogenic.The proband and her children were diagnosed, but her parents were phenotypically normal, in accordance with autosomal dominant inheritance. Conclusions:The novel frameshift variation c.415dupA (p.R139fs) on the exon 8 of PAX6 gene is responsible for congenital iris coloboma with congenital cataract in the pedigree.This is the first report of this novel variation in PAX6 gene.

Type 1 neurofibromatosis in a three-year-old girl with B-lineage acute lymphocytic leukemia:A case report / 中南大学学报(医学版)

Neurofibromatosis 1 (NF1) is an autosomal dominant genetic disease first manifesting in childhood, which affects multiple organs, childhood development and neurocognitive status. These patients have a high predisposition to develop both benign and malignant tumors. On September 30, 2018, a rare case of NF1 with B-lineage acute lymphocytic leukemia (ALL) was treated in the Department of Pediatrics, Third Xiangya Hospital, Central South University. The child presented with café au lait macules (CALM) since the date of birth. And the diagnosis of B-lineage ALL was made by bone marrow cytomorphologic examination and immunological phenotype detection. ETV6/RUNX1 fusion gene was positive. Also, a de novo mutation of c. 2773delT (p. Leu925Ter) was found in the exon of NF1 gene by gene sequencing, which was a nonsense mutation and led to the premature termination of peptide synthesis. Molecular genetic testing is recommended to confirm NF1, particularly in children with only pigmentary features of the diagnostic criteria. NF1-affected individuals should be referred to a specialist of NF1 clinical network for long-term follow-up and surveillance.

Ocular manifestations in a patient with de novo Fabry disease / 영남의대학술지

Fabry disease (FD) is an X-linked, recessively inherited, rare, progressive, disorder of glycosphingolipid metabolism affecting multiple organs resulting in organ dysfunction. It is rare to find only one FD affected subject with a de novo mutation. Here we report a case of a 41-year-old Asian male diagnosed with de novo FD. Comprehensive ophthalmological evaluation was performed using slit lamp, color fundus photography, optical coherence tomography, fluorescein angiography, and indocyanine green angiography. On slit lamp examination, cornea verticillata and slightly tortuous, and aneurysmal dilatation of inferior bulbar conjunctival vessels were observed. Other imaging modalities showed unremarkable findings. Cornea verticillata and inferior bulbar conjunctival vascular abnormalities may be detected earlier than other ocular abnormalities in de novo FDs like hereditary FDs.

A de novo mutation in GNAS cause severe pseudohypoparathyroidism typeⅠa / 临床儿科杂志

Objective To identify the GNAS gene mutation resulting in pseudohypoparathyroidism type Ⅰa (PHP-Ⅰa) in one patient. Methods The clinical data of a patient with pseudohypoparathyroidism type Ⅰa was retrospectively analyzed. All the 13 exons of GNAS were sequenced using Sanger method for the patient and the parents. The distribution of suspected causal mutation was screened in 478 healthy controls. To clarify the origin of the mutation, we performed targeted high-depth sequencing of GNAS exon harboring the mutation for the patient and the parents. Results The clinical data of the patient with the laboratory results of hypocalcaemia, hyperphosphataemia, elevated serum PTH, together with the features of AHO, conformed to the characterization of PHP-Ⅰa. The sequencing of GNAS exons identified a missense mutation (c.479G>C, p.R160P) located at exon 6 in the patient, which was absent in DNA of the parents. The mutation was not reported previously and was not found in the 478 healthy controls. We obtained about 8000-fold coverage from high-depth sequencing of DNA from peripheral blood of the patient and the parents. The disease-associated allele C identified in the patient was not observed in the parents. The number of reads with G allele (3984 reads) was roughly equal to that of C allele (4019 reads) from the targeted reanalysis of DNA of the patient. The results from high-depth sequencing indicated a de novo mutation in maternal germ cells. Conclusions We identified a new GNAS gene mutation (c.479G>C, p.R160P) caused PHP-Ia in a patient. Our results suggested the mutation was a maternal germline de novo mutation.

PCDH19 gene mutations lead to epilepsy with mental retardation limited to females in 2 cases and literature review / 中南大学学报(医学版)

Epilepsy with mental retardation limited to females (EFMR) is a syndrome characterized by early onset heat-sensitive epilepsy of infancy or early childhood and generally limited to females,which previously reported that the cadherin gene superfamily subtype protocadherin 19 (PCDH19)gene is its pathogenic gene.We retrospectively analyzed the clinical data for 2 cases of EFMR patients with PCDH19 mutation diagnosed by Department of Pediatric Neurology of Xiangya Hospital,Central South University in 2015.Literature on PubMed,OMIM and HGMD relevant to this syndrome was reviewed,and the clinical characteristics were summarized accordingly.The 2 cases are consistent with the typical clinical manifestations of EFMR caused by PCDH19 mutations.Their seizures are heat sensitive,with or without screaming,and expressed in various forms.Cognitive impairment or autism-like performance were often identified in these patients,hematuria metabolic diseases screening was normal,no abnormal MRI imaging of the head,and de novo PCDH19 gene mutations were found in their epilepsy gene chip sequencing.It is noteworthy that this disease is very similar to the clinical manifestations of the Dravet syndrome due to the mutations of the neurotype sodium channel αl subunit SCN1A.Therefore,in female patients whose clinical manifestations resemble to Dravet syndrome but SCN1A gene test were negative,EFMR with PCDH19 mutation should be taken into consideration.Early PCDH19 gene testingis of great significance because it not only helps clinicians to understand and analyze the prognosis of this disease,but also offers genetic counseling to the parents.

A Novel POGZ Mutation in a Patient with Intellectual Disability / 中山大学学报(医学科学版)

[Objective]Screening mutation sites of POGZ gene in 100 intellectual disability patients to explore their pathogenesis relationship.[Method]Genomic DNA was isolated from peripheral blood. All exons,exon-intron boundaries,5'UTR and 3'UTR of POGZ were amplified by PCR and PCR products were directly sequenced.[Results]A novel mutation was identified,and the mis?sense mutation disrupted the unique zing-finger like motif of POGZ,which is a critical element for binding Hp1. The mutated POGZ failed to bind with HP1 thus might lose its cell cycle regulation function.[Conclusion]Mutations of POGZ gene weighs more in intel?lectual disability etiology. Screening of POGZ in unexplained intellectual disability patients contributes to their pathogenesis analyze , screening of POGZ in pregnants with family history of intellectual disability can prevent intellectual disability from birthing.

Detection of KIT gene of a case with serious phenotypes of piebaldism / 中山大学学报(医学科学版)

[Objective]To investigate the mutations of KIT gene and SLUG(SNAI2)gene in one patients with piebaldism in Chi?na.[Methods]All coding exons and exon-intron boundaries of KIT gene and SLUG gene were amplified by PCR. The PCR products were sequenced. The DNA samples from 50 normal subjects were also sequenced for control.[Results]The novel mutation,c.860T>A (p.V287E),was detected in patient. This mutation was absent in his parents and the controls ,indicating a de novo mutation. The de?tection result of all coding exons and exon-intron boundaries of SLUG gene was normal.This p.V287E mutation was located in the ex?tracellular ligand-bindingdomain(ectodomain)of KIT,which may generate clash with E249 and disrupt the conformation ofβD andβD/βE of D3 that required for SCF(stem cell factor)binding.[Conclusion]We have identified a novel mutation of KIT gene,c.860T>A(p.V287E),which is probably associated with serious phenotypes of piebaldism.

Two de novo mutations including 1 novel mutation in FBN1 and genotype-phenotype correlation in 2 Chinese Marfan syndrome families / 中国病理生理杂志

[ ABSTRACT] AIM:To investigate the genetic cause of 2 Chinese families with Marfan syndrome .METHODS:The clinical and laboratory investigations were performed in the 2 unrelated Chinese families .Family 1 had 1 patient with cardiac problem.Family 2 had 2 patients:one died, and the other with respiratory and cardiac problems .Next generation sequencing and Sanger sequencing in the Marfan syndrome causal gene FBN1 were performed in the patient , his unaffected sister and the parents of family 1.Sanger sequencing covering all the exons and intron-exon boundaries were performed in the patient and the parents in family 2.Bioinformatic analysis was engaged in the variations unravelled .Fifty healthy indi-viduals were also investigated in the same manner .RESULTS:Both patients were diagnosed with Marfan syndrome .A no-vel mutation c.4685G>A (p.Cys1562Tyr) was detected in the patient of family 1 but was absent in his parents and the unaffected sister .This is a previously unreported novel mutation .In the mutation a conserved Cys was substituted by a Tyr in amino acid 1562 affecting a TGF-βbinding domain and the secondary structure in the encoded protein .We also detected the mutation c.3706T>C (p.Cys1236Arg) in the patient of family 2.It was absent in the unaffected parents , and there-fore was a de novo mutation too.This mutation has been previously reported and known to be associated with neonatal Marfan syndrome .Both mutations were absent in the 50 healthy controls .We also compared the genotype and phenotypes of the 2 families.CONCLUSION:We report 2 de novo mutations in 2 Chinese families with Marfan syndrome .One of the 2 mutations is novel.The phenotype of the mutation c.4685G>A(p.Cys1562Tyr) in family 1 is associated with classical Marfan syndrome, while that of c.3706T>C (p.Cys1236Arg) in family 2 is with neonatal type of Marfan syndrome .De novo mutations may be a cause for a proportion of mutations underlying the disease .The novel mutation also expends the mutational spectrum of the FBN1 gene.