OBJECTIVE: To explore the clinical and genetic characteristics of three children with KBG syndrome. METHODS: Clinical data of the three children from two families who have presented at the First Affiliated Hospital of Zhengzhou University between October 2019 and September 2020 and their family members were collected. Trio-whole exome sequencing (trio-WES) and Sanger sequencing were carried out. RESULTS: All children had feeding difficulties, congenital heart defects and facial dysmorphism. The sib- pair from family 1 was found to harbor a novel de novo heterozygous c.6270delT (p.Q2091Rfs*84) variant of the ANKRD11 gene, whilst the child from family 2 was found to harbor a novel heterozygous c.6858delC (p.D2286Efs*51) variant of the ANKRD11 gene, which was inherited from his mother who had a mild clinical phenotype. CONCLUSION The heterozygous frameshift variants of the ANKRD11 gene probably underlay the disease in the three children. Above findings have enriched the spectrum of the ANKRD11 gene variants.
Female ; Child ; Humans ; Abnormalities, Multiple/genetics* ; Intellectual Disability/genetics* ; Bone Diseases, Developmental/genetics* ; Tooth Abnormalities/genetics* ; Facies ; Repressor Proteins/genetics* ; Mothers ; Mutation

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 explore the clinical features and genetic etiology of a child with Wiedemann-Steiner syndrome. METHODS: A child with WSS who was admitted to the Hematology Department of Tianjin Children's Hospital in May 2021 was selected as the subject. Clinical data of the child was collected. Peripheral blood samples were collected from the child and his parents for the extraction of genomic DNA. The child was subjected to whole exome sequencing, and candidate variant was verified by Sanger sequencing of the child and his parents. RESULTS: The main clinical features of the child have included pancytopenia, growth and mental retardation, and facial dysmorphism. Whole exome sequencing revealed that the child has harbored a heterozygous variant of the KMT2A gene, namely c.7804delA (p.M2602Cfs*39). Sanger sequencing verified the variant to be de novo in origin. The variant was unreported previously and predicted to be pathogenic based on the guidelines of American College of Medical Genetics and Genomics (PVS1+PS2+PM2). CONCLUSION The heterozygous c.7804delA (p.M2602Cfs*39) variant of the KMT2A gene probably underlay the WSS in this child. Above finding has enriched the mutational spectrum and clinical phenotypes of the KMT2A gene.
Humans ; Abnormalities, Multiple/genetics* ; Intellectual Disability/genetics* ; Mutation ; Syndrome

OBJECTIVE: To explore the clinical phenotype and genetic basis of a neonate with Au-Kline syndrome (AKS). METHODS: Clinical data and result of genetic testing of a neonate with AKS who was admitted to the Affiliated Provincial Children's Hospital of Anhui Medical University in January 2021 were retrospectively analyzed. Relevant literature was searched from the Wanfang Data Knowledge Service Platform, China National Knowledge Infrastructure and PubMed databases using key words "Au Kline syndrome", "Au-Kline syndrome", "HNRNPK" and "AKS". The research period was set as from January 1, 2000 to December 31, 2020. RESULTS: The male newborn has manifested feeding difficulties, hypotonia, absence of the upper jaw to the uvula and facial dysmorphism. Trio-whole exome sequencing revealed that he has harbored a frameshift c.478dupA (p.Ile160AsnfsTer7) variant of the HNRNPK gene, which was varified by Sanger sequencing to have a de novo origin. The variant has not been included in the databases. Based on the guidelines from the American College of Medical Genetics and Genomics, the variant was rated as pathogenic (PVS1+PS2+PM2_Supporting). Literature retrieval has identified 14 children with AKS and de novo mutations of the HNRNPK gene. Their clinical manifestations have included growth and motor retardation, various degree of mental retardation, facial dysmorphism and a high frequency of congenital heart malformations. CONCLUSION The AKS in this child may be attributed to the c478dupA frameshifting variant of the HNRNPK gene. Diagnosis of AKS should be suspected for children with mental retardation and multiple congenital malformation syndromes including Kabuki syndrome.
Humans ; Male ; Abnormalities, Multiple/genetics* ; Genetic Testing ; Heterogeneous-Nuclear Ribonucleoprotein K/genetics* ; Intellectual Disability/genetics* ; Mutation ; Retrospective Studies ; Infant, Newborn

OBJECTIVE: To explore the genetic basis for a child with facial dysmorphism and multiple malformations. METHODS: The child, born at 34⁺⁶ weeks' gestation due to premature rupture of amniotic membrane, dichorionic diamniotic twinning and gestational diabetes, was subjected to chromosomal karyotyping analysis and copy number variations sequencing (CNV-seq). RESULTS: The child was found to have facial dysmorphism, hypospadia, cryptorchidism and hypotonia. He was found to have a 46,XY,del(3)(p26) karyotype in addition with a 9.80 Mb deletion (chr3: 60 000-9 860 000) encompassing 33 protein coding genes. CONCLUSION The 3p26.3p25.3 deletion probably underlay the multiple malformations in this child. Continuous follow-up is required to improve his quality of life.
Humans ; Male ; Chromosome Deletion ; DNA Copy Number Variations ; Quality of Life ; Abnormalities, Multiple/genetics* ; Phenotype

A full-term female infant was admitted at 5 hours after birth due to heart malformations found during the fetal period and cyanosis once after birth. Mmultiple malformations of eyes, face, limbs, and heart were noted. The whole-exome sequencing revealed a pathogenic heterozygous mutation, c.2428C>T(p.Arg810^*), in the BCOR gene. The infant was then diagnosed with oculo-facio-cardio-dental syndrome. He received assisted ventilation to improve oxygenation and nutritional support during hospitalization. Right ventricular double outlet correction was performed 1 month after birth. Ocular lesions were followed up and scheduled for elective surgery. The possibility of oculo-facio-cardio-dental syndrome should be considered for neonates with multiple malformations of eyes, face, and heart, and genetic testing should be performed as early as possible to confirm the diagnosis; meanwhile, active ophthalmic and cardiovascular symptomatic treatment should be given to improve the prognosis.
Female ; Humans ; Infant ; Infant, Newborn ; Male ; Abnormalities, Multiple/therapy* ; Cataract/genetics* ; Cyanosis ; Proto-Oncogene Proteins ; Repressor Proteins/genetics* ; Heart Defects, Congenital/genetics*

OBJECTIVE: To summarize the clinical features and biological characteristics of Helsmoortel Van der Aa syndrome (HVDAS) due to hotspot mutations of the ADNP gene in order to facilitate early diagnosis. METHODS: Clinical data and result of genetic testing for a girl with HVDAS due to hotspot mutation of the ADNP gene was summarized. Related literature was also reviewed. RESULTS: The patient, a 2-year-old girl, had presented with growth retardation, facial dysmorphism, psychomotor and language delay and recurrent respiratory infections. Whole exome sequencing revealed that she has harbored a heterozygous c.2496_2499delTAAA (p.Asn832Lysfs*81) variant of the ADNP gene, which was not found in either of her parents. CONCLUSION Although the typical features of the HVDAS have included intellectual disability and autism spectrum disorders, growth retardation and premature primary tooth eruption may also be present. In addition, the phenotypic difference among individuals carrying hot spot variants of the ADNP gene was not prominent.
Humans ; Female ; Child, Preschool ; Intellectual Disability/genetics* ; Homeodomain Proteins/genetics* ; Nerve Tissue Proteins/genetics* ; Abnormalities, Multiple/genetics* ; Mutation ; Rare Diseases ; Growth Disorders/genetics*

OBJECTIVE: To explore the genetic basis for a child with multiple malformations. METHODS: A child who had presented at Shanxi Provincial Children's Hospital in February 2021 was selected as the study subject. Clinical data of the patient was collected, and whole exome sequencing (WES) was carried out to screen pathogenic variants associated with the phenotype. Candidate variant was validated by Sanger sequencing of her family members. RESULTS: The child had normal skin, but right ear defect, hemivertebral deformity, ventricular septal defect, arterial duct and patent foramen ovale, and separation of collecting system of the left kidney. Cranial MRI showed irregular enlargement of bilateral ventricles and widening of the distance between the cerebral cortex and temporal meninges. Genetic testing revealed that she has harbored a heterozygous variant of NM_178014.4: c.217A>G (p.Met73Val) in the TUBB gene, which was unreported previously and predicted to be likely pathogenic based on the guidelines from the American College of Medical Genetics and Genomics (ACMG). The child was diagnosed with Complex cortical dysplasia with other brain malformations 6 (CDCBM6). CONCLUSION CDCBM is a rare and serious disease with great genetic heterogeneity, and CDCBM6 caused by mutations of the TUBB gene is even rarer. Above finding has enriched the variant and phenotypic spectrum of the TUBB gene, and provided important reference for summarizing the genotype-phenotype correlation of the CDCBM6.
Humans ; Child ; Female ; Abnormalities, Multiple ; Blood Group Antigens ; Family ; Malformations of Cortical Development/genetics* ; Brain ; Mutation

Objective: To analyze the clinical and genetic characteristics of pediatric patients with dual genetic diagnoses (DGD). Methods: Clinical and genetic data of pediatric patients with DGD from January 2021 to February 2022 in Peking University First Hospital were collected and analyzed retrospectively. Results: Among the 9 children, 6 were boys and 3 were girls. The age of last visit or follow-up was 5.0 (2.7,6.8) years. The main clinical manifestations included motor retardation, mental retardation, multiple malformations, and skeletal deformity. Cases 1-4 were all all boys, showed myopathic gait, poor running and jumping, and significantly increased level of serum creatine kinase. Disease-causing variations in Duchenne muscular dystrophy (DMD) gene were confirmed by genetic testing. The 4 children were diagnosed with DMD or Becker muscular dystrophy combined with a second genetic disease, including hypertrophic osteoarthropathy, spinal muscular atrophy, fragile X syndrome, and cerebral cavernous malformations type 3, respectively. Cases 5-9 were clinically and genetically diagnosed as COL9A1 gene-related multiple epiphyseal dysplasia type 6 combined with NF1 gene-related neurofibromatosis type 1, COL6A3 gene-related Bethlem myopathy with WNT1 gene-related osteogenesis imperfecta type XV, Turner syndrome (45, X0/46, XX chimera) with TH gene-related Segawa syndrome, Chromosome 22q11.2 microduplication syndrome with DYNC1H1 gene-related autosomal dominant lower extremity-predominant spinal muscular atrophy-1, and ANKRD11 gene-related KBG syndrome combined with IRF2BPL gene-related neurodevelopmental disorder with regression, abnormal movement, language loss and epilepsy. DMD was the most common, and there were 6 autosomal dominant diseases caused by de novo heterozygous pathogenic variations. Conclusions: Pediatric patients with coexistence of double genetic diagnoses show complex phenotypes. When the clinical manifestations and progression are not fully consistent with the diagnosed rare genetic disease, a second rare genetic disease should be considered, and autosomal dominant diseases caused by de novo heterozygous pathogenic variation should be paid attention to. Trio-based whole-exome sequencing combining a variety of molecular genetic tests would be helpful for precise diagnosis.
Humans ; Abnormalities, Multiple ; Retrospective Studies ; Intellectual Disability/genetics* ; Bone Diseases, Developmental/complications* ; Tooth Abnormalities/complications* ; Facies ; Muscular Dystrophy, Duchenne/complications* ; Muscular Atrophy, Spinal/complications* ; Carrier Proteins ; Nuclear Proteins

OBJECTIVE: To analyze the clinical data and genetic characteristics of a child with fibrocartilage hyperplasia type 1 (FBCG1). METHODS: A child who was admitted to Gansu Provincial Maternity and Child Health Care Hospital on January 21, 2021 due to severe pneumonia and suspected congenital genetic metabolic disorder was selected as the study subject. Clinical data of the child was collected, and genomic DNA was extracted from peripheral blood samples from the child and her parents. Whole exome sequencing (WES) was carried out, and candidate variants were verified by Sanger sequencing. RESULTS: The patient, a 1-month-old girl, had presented with facial dysmorphism, abnormal skeletal development, and clubbing of upper and lower limbs. WES revealed that she has harbored compound heterozygous variants c.3358G>A/c.2295+1G>A of the COL11A1 gene, which has been associated with fibrochondrogenesis. Sanger sequencing has verified that the variants have been respectively inherited from her father and mother, both of whom were phenotypically normal. Based on the guidelines from the American College of Medical Genetics and Genomics (ACMG), the c.3358G>A variant was graded as likely pathogenic (PM1+PM2_Supporting+PM3+PP3), and so was the c.2295+1G>A variant (PVS1＋PM2_Supporting). CONCLUSION The compound heterozygous variants c.3358G>A/c.2295+1G>A probably underlay the disease in this child. Above finding has facilitated definite diagnosis, genetic counseling for her family.
Female ; Humans ; Infant ; Abnormalities, Multiple ; Collagen Type XI/genetics* ; Genetic Counseling ; Genomics ; Mutation