OBJECTIVE: To analyze the genotype and clinical phenotype of a 3-month-old female infant featuring unresponsiveness. METHODS: The infant was subjected to genetic testing, and her clinical features were compared with syndromes associated with variants of the candidate gene. RESULTS: The patient has featured long fingers, long and overlapped toes, musk-like face, blepharophimosis, ptosis, and lacrimal duct anomaly. She was found to harbor a heterozygous de novo variant NM_012330.3: c.3040C>T (p.Gln1014*) in exon 16 of the KAT6B gene. Her clinical phenotype and genotype have both conformed to Say-Barber-Biesecker-Young-Simpson syndrome (SBBYSS). CONCLUSION The child was diagnosed with SBBYSS syndrome due to the c.3040C>T (p.Gln1014*) variant of the the KAT6B gene. Discovery of the unique features has expanded the phenotypic spectrum of this syndrome.
Female ; Humans ; Blepharophimosis/genetics* ; Blepharoptosis ; Genotype ; Histone Acetyltransferases ; Infant

Blepharophimosis ; diagnosis ; genetics ; Humans ; Male ; Middle Aged ; Pedigree ; Phenotype ; Skin Abnormalities ; diagnosis ; genetics ; Urogenital Abnormalities

OBJECTIVE: To analyze the clinical manifestations and gene variants of patients with blepharophimosis, ptosis and epicanthus inversus syndrome (BPES). METHODS: Clinical data of 7 pedigrees affected with BPES were collected, and genomic DNA was extracted from peripheral blood samples of the probands and their relatives. All exons of the FOXL2 gene were subjected to Sanger sequencing. Those with negative findings were further screened by targeted capture and next generation sequencing (NGS) and microarray analysis. Pathogenicity of candidate variants were predicted by search of PubMed and related databases, and the impact of the variants was interpreted by protein prediction software. Diagnosis was confirmed by clinical phenotype, medical history and mutation analysis. RESULTS: A pathogenic variant was identified in six of the 7 pedigrees, which included four known pathogenic variants and one novel FOXL2 c.299dupA variant. A heterozygous 3q22.3q23 deletion, which encompassed the FOXL2 gene, was identified in another pedigree.As predicted, the c.299dupA frameshift mutation of FOXL2 gene can lead to the premature termination of protein translation, which is pathogenic. CONCLUSION A novel and 5 known pathogenic variants have been identified in six pedigrees affected with BPES by the combined Sanger sequencing, target capture NGS and microarray analysis. Above findings have enabled genetic counseling and prenatal diagnosis for these pedigrees.
Blepharophimosis/genetics* ; Forkhead Box Protein L2/genetics* ; Forkhead Transcription Factors/genetics* ; Humans ; Mutation ; Pedigree ; Phenotype ; Skin Abnormalities ; Urogenital Abnormalities

OBJECTIVE To determine the genetic cause of a child with blepharophimosis, ptosis, and epicanthus inverses syndrome and tetralogy of Fallot, and to correlate the phenotype with the genotype. METHODS Routine G-banding has been previously performed on the patient and her parents. Chromosome microarray analysis (CMA) was performed for the three individuals and the fetus. RESULTS Chromosomal analysis has suggested normal karyotypes for the child and her parents. However, a de novo 8.9 Mb deletion on chromosome 3q22.1-q23 was detected by CMA. The deleted region has encompassed 74 genes including 41 disease-related genes, and this is also the most frequent region involved in interstitial 3q deletion. Patients with deletion of this region often have a common feature of dysplasia of eyelids, as well as a spectrum of other anomalies according to different breakpoints, including microcephaly, skeletal anomalies, congenital heart defects, cranial anomalies, intellectual disability and developmental delay. The patient's phenotype was in accordance with such spectrum. Her parents and sib did not show this variation by CMA. CONCLUSION The de novo interstitial deletion of 3q22.1-q23 probably underlies the main clinical manifestation in this child. CMA can provide more detailed information and allow further investigation of the genotype-phenotype correlation.
Blepharophimosis ; genetics ; Child, Preschool ; Chromosomes, Human, Pair 3 ; Female ; Humans ; Mitochondrial Proteins ; genetics ; Phenotype ; Ribosomal Proteins ; genetics ; Skin Abnormalities ; genetics ; Tetralogy of Fallot ; genetics ; Urogenital Abnormalities ; genetics

OBJECTIVE: To explore the genetic basis for a child suspected for Say-Barber-Biesecker-Young-Simpson syndrome. METHODS: Genomic DNA was extracted from peripheral blood samples of the child and her parents. Whole exome sequencing was carried out for the proband. Suspected variants were validated by Sanger sequencing. The impact of the variants was predicted by bioinformatic analysis. RESULTS: The child was found to harbor a de novo missense variant c.2623C>T (p.Asp875Tyr) in exon 13 of the KAT6B gene. The variant was previously unreported, and was not recorded in the major allele frequency database and predicted to be pathogenic based on PolyPhen-2, MutationTaster and PROVEAN analysis. As predicted by UCSF chimera and CASTp software, the variant can severely impact the substrate-binding pocket of histone acetyltransferase, resulting in loss of its enzymatic activity. Based on standards and guidelines by the American College of Medical Genetics and Genomics, the variant was classified to be likely pathogenic (PS2+PM2+PP3). CONCLUSION The child's condition may be attributed to the de novo missense c.2623C>T (p.Asp875Tyr) variant of the KAT6B gene.
Blepharophimosis ; Child ; Congenital Hypothyroidism ; Facies ; Female ; Heart Defects, Congenital ; Histone Acetyltransferases/genetics* ; Humans ; Intellectual Disability ; Joint Instability ; Mutation ; Phenotype

Abnormalities, Multiple ; genetics ; Amino Acid Sequence ; Blepharophimosis ; genetics ; Blepharoptosis ; genetics ; Eyelids ; abnormalities ; Female ; Forkhead Box Protein L2 ; Forkhead Transcription Factors ; genetics ; Humans ; Male ; Molecular Sequence Data ; Mutation ; Syndrome

To analyze congenital sensorineural hearing loss combined with blepharophimosis-ptosis-epicanthus inversus syndrome (BPES). For the case of cochlear implantation to child with congenital sensorineural deafness combined BPES, accomplish routine examination and assessment, combining with literature to analyze the clinical diagnosis of this disease and its significance. Sensorineural hearing loss is a common congenital diseases with neonatal incidence of 1 per thousand - 3 per thousand, 50%-70% of deafness is associated with genetic factors, the incidence of congenital sensorineural hearing loss combined with eye disease is about 40%-60%, mainly reflected in ametropia and retinopathy. BPES's main clinical manifestations is blepharophimosis, ptosis, epicanthus inversus, and telecanthus. BPES is a rare autosomal dominant disease caused by FOXL 2 gene mutation, sometimes associated with retarded growth, delayed development, congenital heart disease, and microcephaly. Suffering from both sensorineural hearing loss and BPES is rare in reported literature. This case is diagnosed by clinical examination, without visual impairment. Facial nerve dysplasia has been found during the surgery. For congenital deafness patients with eye disease or other diseases, timely and correct diagnosis has important clinical significance, which can improve the diagnostic rate and make it coming true to early intervention, and then, effectively improve the quality of the patients. There are few literature reports, of patients with two kinds of genetic diseases. Our inference is that the cases are rare or the patients has visited different departments and ignored the other systems' signs. Therefore, in such doubtful cases, we should do the professional comprehensive examination in daily clinical work in order to avoid missed diagnosis or delayed treatment and intervention. By analyzing this case, the patient may also suffer from facial nerve dysplasia. Preoperatively viewing CT scan and operatively facial nerve monitor being used can avoid the occurrence of surgical complications.
Blepharophimosis ; complications ; genetics ; Child ; Forkhead Transcription Factors ; Hearing Loss, Sensorineural ; congenital ; diagnosis ; Humans ; Mutation ; Skin Abnormalities ; complications ; genetics ; Urogenital Abnormalities ; complications ; genetics

BACKGROUNDBlepharophimosis ptosis epicanthus inversus syndrome (BPES) is a rare congenital ophthalmic disorder, characterized by congenital eyelid malformation including bilateral ptosis, shortening of the horizontal eyelid fissure, epicanthus inversus, and increased distance between the inner canthi. In this research, we studied the histological structure and ultrastructure of medial canthal ligament of patients with BPES.

METHODSThirty patients with BPES who received plastic surgery at the Zhongshan Ophthalmic Center from March 2006 to January 2008 were studied. There were 17 males and 13 females with an average age of (8.73 +/- 3.37) years (3 - 31 years). The medial canthal ligaments of patients were collected during the plastic surgery to analyze the histological structure by hematoxylin and eosin (HE), Congo red, van Gieson's (VG), Masson trichrome and aldehyde-fuchsin staining. The ultrastructures of the medial canthal ligaments were also analyzed by scanning electron microscopy (SEM) and transmission electron microscopy (TEM). Fifteen samples of medial canthal ligament from healthy persons with an average age of (9.02 +/- 3.12) years (6 - 30 years) were collected as a control group.

RESULTSMorphological and histological study showed that the medial canthal ligaments of BPES patients were composed of collagen fibers, a few elastic fibers and striated muscles. The collagen fibers assemblies were disorganized and the fibrous connective tissues were undergoing hyaline degeneration. The karyopycnosis of fibroblasts was located among the collagen fibrils and the numbers of fibroblasts were decreased. Ultrastructural study with SEM showed that the collagen fibers were larger than normal, irregular and loose. Parts of the collagen fibers were broken and had a coarse surface. Ultrastructural study with TEM showed that the fibroblasts had less cytoplasm, fewer organelles and the nucleus displayed pyknosis.

CONCLUSIONSThe medial canthal ligament in BPES patients is composed chiefly of collagen fibers. The collagen fibers of medial canthal ligaments in BPES patients are disorganized and hyaline degeneration is present. The study revealed that the medial canthal ligament of BPES patients might have congenital dysplasia.

Adolescent ; Adult ; Blepharophimosis ; genetics ; pathology ; Blepharoptosis ; genetics ; pathology ; Child ; Child, Preschool ; Eyelids ; abnormalities ; pathology ; ultrastructure ; Female ; Humans ; Male ; Microscopy, Electron, Scanning ; Microscopy, Electron, Transmission ; Syndrome

OBJECTIVE: To analyze the clinical and molecular genetics features of a family affected with Say-Barber-Biesecker-Young-Simpson syndrome (SBBYSS). METHODS: High-throughput sequencing was used to detect copy number variations (CNVs) and pathogenic variant within the whole exome of the affected child. RESULTS: No pathogenic CNV was found in the child, while exome sequencing identified a heterozygous c.3367_c.3370delAGAA (p.Arg1123Argfs*6) frameshifting variant in the exon 16 of the KAT6B gene. The same variant was not found in either parent. CONCLUSION The c.3367_c.3370delAGAA (p.R1123Rfs*6) probably underlies the disease in the affected child. Above finding has facilitated genetic counseling and prenatal diagnosis for the family.
Blepharophimosis ; genetics ; Child ; Congenital Hypothyroidism ; genetics ; DNA Copy Number Variations ; Facies ; Female ; Heart Defects, Congenital ; genetics ; Histone Acetyltransferases ; genetics ; Humans ; Intellectual Disability ; genetics ; Joint Instability ; genetics ; Mutation ; Phenotype ; Pregnancy

OBJECTIVETo screen for FOXL2 gene mutations in 6 patients with blepharophimosis, ptosis, and epicanthus inversus syndrome (BPES), and explore their genotype-phenotype correlation.

METHODSPeripheral venous blood samples were collected from the patients for the extraction of genomic DNA. PCR and Sanger sequencing were employed to analyze the coding region and flanking sequences of the FOXL2 gene. Pathogenicity of the identified mutations was verified through literature review and bioinformatic analysis.

RESULTSA heterozygous c.672_701dup30 mutation was found in the probands from the two familial cases, while three heterozygous mutations (two were novel), namely c.462_468del (p.Pro156Argfs*113), c.251T to A (p.Ile84Asn) and c.988_989insG (p.Ala330Glyfs*204) were detected in the three sporadic cases. Literature review and bioinformatic analysis indicated that all these mutations are pathogenic.

CONCLUSIONIdentification of causative mutations in the BPES patients has provided a basis for genetic counseling and reproductive guidance. The novel mutations have enriched the mutation spectrum of the FOXL2 gene.

Adult ; Asian Continental Ancestry Group ; genetics ; Base Sequence ; Blepharophimosis ; diagnosis ; genetics ; China ; Female ; Forkhead Box Protein L2 ; Forkhead Transcription Factors ; genetics ; Genetic Association Studies ; Humans ; Male ; Molecular Sequence Data ; Pedigree ; Skin Abnormalities ; diagnosis ; genetics ; Urogenital Abnormalities ; diagnosis ; genetics ; Young Adult