OBJECTIVE: To retrospectively analyze 11 Chinese pedigrees affected with Leber congenital amaurosis (LCA) and summarize the clinical manifestations and genetic characteristics of patients. METHODS: Eleven Chinese pedigrees with probands diagnosed with LCA at the First Affiliated Hospital of Zhengzhou University from January 2020 to December 2023 were selected as the study subjects. Clinical phenotypic data of the probands were collected. Peripheral blood samples of patients and their family members were collected for the extraction of genomic DNA and whole exome sequencing. Candidate variants were validated by Sanger sequencing, qPCR assay and search of relevant databases and bioinformatic analysis. Based on the guidelines from the American College of Medical Genetics and Genomics (ACMG), a diagnosis was made based on the patient's clinical phenotype, family history, and results of genetic testing. Prenatal diagnosis was provided for relevant families upon their subsequent pregnancies. This study has been approved by the Medical Ethnic Committee of the Hospital (Ethics No.: KS-2018-KY-36). RESULTS: Pedigrees 1 to 9 showed clinical features consistent with LCA and were diagnosed through genetic testing. Pedigrees 10 and 11, whilst suspected for having LCA, only had heterozygous variants detected. In total 11 novel variants were detected, including c.385C>T (p.Gln129*), c.42A>C (p.Lys14Asn) and c.1018dupA (p.Thr340Asnfs*67) of the AIPL1 gene, c.1196_1200delAAAAT (p.Asn400Thrfs*31) and exon 6-12 deletion of the SPATA7 gene, c.251A>T (p.Gln84Leu), c.875_892dupGTGCCTGGAA (p.Ser292_Gln297dup) and c.444delC (p.Ser150Glnfs*37) of the CRX gene, c.1368C>A (p.Cys456*) and c.2512A>T (p.Lys838*) of the CRB1 gene and c.3221delC (p.Pro1074Leufs*5) of the RPGRIP1 gene. CONCLUSION The phenotypic and genetic heterogeneity of LCA has posed substantial difficulty for clinical diagnosis and subtyping of the disease. Our retrospective analysis has identified novel pathogenic variants and multiple subtypes of LCA. The discovery of novel pathogenic variants and phenotypic characterization of LCA subtypes may enhance the understanding of disease etiology and clinical heterogeneity, and provide a basis for diagnosis, treatment, and genetic counseling.
Adult ; Child ; Child, Preschool ; Female ; Humans ; Male ; China ; Eye Proteins/genetics* ; Genetic Testing ; Genetic Variation ; Leber Congenital Amaurosis/diagnosis* ; Membrane Proteins/genetics* ; Mutation ; Nerve Tissue Proteins/genetics* ; Pedigree ; Phenotype ; Retrospective Studies ; East Asian People/genetics* ; Adaptor Proteins, Signal Transducing

PURPOSE: To report the incidence and new findings of abnormal brain imaging studies associated with patients initially diagnosed with Leber's congenital amaurosis (LCA) without definite systemic abnormalities and to determine the need for brain imaging studies in these patients. METHODS: A retrospective review of medical records was performed in 83 patients initially diagnosed as LCA and without definite systemic abnormalities before the age of 6 months in 2 tertiary referral centers. Brain magnetic resonance imaging was performed in 31 of 83 patients (37.3%). RESULTS: Six of 31 patients (19%) had radiologically documented brain abnormalities. Two patients had cerebellar vermis hypoplasia, 1 patient showed an absence of septum pellucidum, 2 subjects showed mild external hydrocephalus, and 1 patient was found to have a small cerebellum. CONCLUSIONS: Approximately one fifth of the LCA patients in whom brain imaging was performed were associated with brain abnormalities, including the absence of septum pellucidum, which has not been documented in the literature. Brain imaging is mandatory in patients primarily diagnosed with LCA, even without definite neurologic or systemic abnormalities.
Brain/*pathology ; Cerebellum/pathology ; Female ; Humans ; Hydrocephalus/pathology ; Infant ; Leber Congenital Amaurosis/*diagnosis ; *Magnetic Resonance Imaging ; Retrospective Studies ; Septum Pellucidum/pathology