Genetic analysis of two children with Coffin-Siris syndrome due to variants of ARID1B gene / 中华医学遗传学杂志

OBJECTIVE@#To explore the genetic basis of two children with unexplained psychomotor developmental delay and facial dysmorphisms suggestive of Coffin-Siris syndrome (CSS).@*METHODS@#A boy and a girl suspected for CSS at the 980th Hospital of the People's Liberation Army Joint Service Support Force respectively in July 2019 and January 2021, and seven members from their families, were selected as the study subjects. Clinical data and family history of the children were collected, and detailed physical examination was carried out, in addition with laboratory and related auxiliary examinations. Potential variants and copy number variations (CNVs) were detected by whole exome sequencing (WES) and copy number variation sequencing (CNV-seq).@*RESULTS@#Child 1, an 8-month-old female, had featured microcephaly, atrial septal defect, curving of fifth finger/toe, and low limb muscle tone. Child 2 was a 2.5-year-old male with language delay, social impairment, dense hair but no curving of the fifth fingers. Genetic testing revealed that child 1 had loss of heterozygosity for exons 8 to 21 of the ARID1B gene, which was unreported previously. Family verification showed that both of her parents were of the wild type. Based on the guidelines from the American College of Medical Genetics and Genomics (ACMG) and American Society of Molecular Pathology (AMP), the variant was rated as pathogenic (PVS1+PS2+PM2-supporting). Child 2 was found to harbor a heterozygous c.4263-6 (IVS17) T>G variant of the ARID1B gene. Transcriptome sequencing confirmed that the variant can affect the normal splicing, resulting in retention of a 5 bp sequence in intron 17. Family verification showed that both of his parents were of the wild type. Based on the guidelines from the ACMG, the variant was rated as pathogenic (PS2+PM2-supporting+PP3+PS3).@*CONCLUSION@#WES and RNA-seq have confirmed the diagnosis of CSS in both children. Discovery of the novel variants has expanded the spectrum of pathogenic mutations underlying CSS, and provided a basis for the genetic counseling.

Rol de la laparoscopia en el manejo del síndrome OHVIRA: reporte de un caso y su relación con la endometriosis / Role of laparoscopy in the management of OHVIRA syndrome: a case report and its relation to endometriosis

El síndrome de hemivagina obstruida y anomalía renal ipsilateral (OHVIRA) es producido por una alteración en el desarrollo de los conductos de Müller y Wolff en la vida fetal. El síndrome es poco frecuente, se reporta una prevalencia de 1/2.000 a 1/28.000 casos. La endometriosis se presenta en un 19% de los casos complicando esta patología. El tratamiento del síndrome OHVIRA consiste en resecar el tabique vaginal drenando el hematocolpos. Hasta el momento no existe un consenso en recomendar la realización de una laparoscopia diagnóstica. El objetivo de este estudio es reportar la eventual importancia de la laparoscopia diagnóstica/terapéutica como parte del manejo del síndrome OHVIRA.

Obstructed hemivagina and ipsilateral renal anomaly (OHVIRA) syndrome is caused by a defect in the development of Müllerian and Wolffian ducts at fetal life. The syndrome is uncommon, with a reported prevalence of 1/2,000 to 1/28,000 cases. Endometriosis is present in 19% of cases complicating this pathology. Treatment of OHVIRA syndrome consists in resecting the vaginal septum and draining the hematocolpos. Until now there isnt an agreement on recommending diagnostic laparoscopy as part of the treatment. The aim of this study is to report the importance of diagnostic/therapeutic laparoscopy in the management of OHVIRA syndrome.

Síndrome de Wildervanck: reporte de un caso clínico / Wildervanck syndrome: clinical case report

El síndrome de Wildervanck (cérvico-óculo-acústico) es una patología muy rara, caracterizada por la tríada clásica de fusión de vértebras cervicales o anomalía de Klippel-Feil, síndrome de Duane (paresia del VI par craneal) e hipoacusia. Se han descrito, además, otras afecciones a nivel vascular, cardíaco y musculoesquelético. En este caso clínico, describimos a una paciente que cumple la tríada cardinal, además de presentar datos clínicos adicionales que no han sido reportados con anterioridad, lo cual contribuye a la ampliación del fenotipo de la enfermedad. Asimismo, realizamos una revisión de la literatura respecto a este síndrome

Wildervanck syndrome (also known as cervico-oculo-acoustic dysplasia) is a very rare disease, characterized by the typical triad of cervical vertebral fusion or Klippel-Feil anomaly, Duane syndrome (paresis of the sixth cranial nerve), and hearing loss. Other vascular, cardiac, and musculoskeletal conditions have also been described. In this case report, we describe a patient who met the cardinal triad and also presented additional clinical data that have not been previously reported, which contribute to broadening the disease phenotype. We have also reviewed the bibliography related to this syndrome.

Características clínicas e fonoaudiológicas de neonatos hospitalizados em uma Unidade de Tratamento Intensivo neonatal com suspeita de doença genética / Clinical and speech-language pathology characteristics of neonates hospitalized in a neonatal Intensive Care Unit with suspected genetic disease / Características clínicas y de patología del habla y lenguaje de neonatos hospitalizados en una Unidad de Cuidados Intensivos neonatales con sospecha de enfermedad genética

Introdução: A prematuridade é um fator de risco para o crescimento e o desenvolvimento dos neonatos. Objetivo: Analisar as características clinicas e fonoaudiológicas de neonatos hospitalizados na unidade de tratamento intensivo (UTI) neonatal com suspeita de doença genética. Material e Método:Estudo transversal descritivo, conduzido em um hospital na região sul do Brasil com coleta de dados entre novembro de 2020 e setembro de 2021. Todos os neonatos que se encontravam internados na UTI, atendidos pelo Sistema Único de Saúde e que apresentavam suspeita de etiologias genéticas foram acompanhados pela equipe de Fonoaudiologia. Foram analisados todos os prontuários dos recém-nascidos com suspeita de alteração genética, extraindo-se os dados médicos e fonoaudiológicos. Resultados:A amostra foi constituída por 14 neonatos prematuros com média de idade gestacional de 36 semanas e 5 dias e uma média de tempo de nascimento, no momento da avaliação fonoaudiológica, de 14,6 dias de vida. No que se refere às comorbidades, 71,4% dos recém-nascidos apresentavam alguma malformação, sendo múltiplas na maior parte dos casos (64,29%). Todos os neonatos estavam fazendo uso de via enteral de alimentação durante a avaliação fonoaudiológica. Na avaliação de reflexos orais, observou-se que houve um predomínio de pacientes com reflexo de procura débil, sendo que a maior parte apresentava reflexo de sucção presente. Conclusões: Pode-se afirmar que, neste estudo, a amostra foi composta por pacientes principalmente prematuros que apresentavam malformações múltiplas e que todos faziam uso de via alternativa de alimentação sugerindo, assim, a necessidade de atendimento fonoaudiológico como parte da assistência multidisciplinar desses neonatos. (AU)

Introduction: Prematurity is a risk factor for the growth and development of neonates. Objective: To analyze clinical and speech therapy characteristics of neonates hospitalized in the neonatal intensive care unit with suspected genetic disease. Method: Descriptive cross-sectional study conducted in a hospital in southern Brazil with data collection between November 2020 and September 2021. All neonates who were hospitalized in the ICU attended by the public health system and who were suspected of having genetic etiologies were followed up by the Speech-Language Pathology team. All newborn`s medical records with suspected genetic alterations were analyzed and the medical and the speech-language pathology data were analyzed. Results: The sample consisted of 14 premature neonates with a mean gestational age of 36 weeks and 5 days and a mean time of birth, at the time of the speech-language pathology assessment, of 14.6 days of life. Regarding to comorbidities, 71.4% of newborns had some malformation, being multiple in most cases (64.29%). All neonates were using enteral feeding at the time of the speech-language evaluation. At the oral reflexes evaluation it was observed that there was a predominance of patients with a weak rooting reflex and most of them had a present sucking reflex. Conclusions: In this study the sample consisted of mainly premature patients who had multiple malformations and all of them used an alternative feeding route, thus suggesting the demand for speech therapy as part of the multidisciplinary care of these neonates. (AU)

Introducción: La prematuridad es un factor de riesgo para el crecimiento y desarrollo de los recién nacidos. Objetivo: Analizar las características clinicas y de terapia del habla de recién nacidos hospitalizados en la unidad de cuidados intensivos neonatales (UCI) con sospecha de enfermedad genética. Método: Estudio transversal descriptivo realizado en un hospital en la región del Sur de Brasil. Todos los recién nacidos que fueron hospitalizados en la UTI y que tenían sospecha de tener etiologías genéticas, fueron atendidos por el equipo de Patología del Habla y Lenguaje. Se analizaron todas las historias clínicas de los recién nacidos con sospecha de alteraciones genéticas, extrayéndose datos médicos y de patología del habla y del lenguaje. Resultados: La muestra estuvo constituida por 14 neonatos prematuros con una edad gestacional media de 36 semanas. En cuanto a las comorbilidades, el 71,4% de los recién nacidos presentó alguna malformación, siendo múltiples en la mayoría de los casos (64,29%). Con respecto a los datos de la evaluación de la patología del habla y el lenguaje, todos los recién nacidos estaban usando alimentación enteral. En la evaluación de los reflejos orales, se observó que hubo un predominio de pacientes con reflejo de búsqueda débil, y la mayoría de ellos tenían presente el reflejo de succión. Conclusiones: Se puede decir que en este estudio la muestra estuvo compuesta principalmente por pacientes prematuros, que presentaban plurimalformaciones y que todos utilizaban una vía alternativa de alimentación, sugiriendo así, la necesidad de la fonoaudiología como parte del cuidado multidisciplinario de estos neonatos. (AU)

Clinical and genetic characteristics of 9 rare cases with coexistence of dual genetic diagnoses / 中华儿科杂志

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.

Genetic analysis of a child with Complex cortical dysplasia with other brain malformations type 6 due to a p.M73V variant of TUBB gene / 中华医学遗传学杂志

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.

Helsmoortel-Van der Aa syndrome due to hotspot mutation of ADNP gene and a literature review / 中华医学遗传学杂志

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.

Prenatal diagnosis of a case with Schuurs-Hoeijmakers syndrome / 中华医学遗传学杂志

OBJECTIVE@#To explore the genetic basis for a fetus with multiple malformations.@*METHODS@#Clinical data of the fetus was collected, Amniotic fluid sample of the fetus was subjected to conventional G-banded karyotyping, low-depth whole genome copy number variants detection and whole exome sequencing (WES). Candidate variant was verified by Sanger sequencing of the fetus and its parents.@*RESULTS@#Prenatal ultrasound scan at 21+5 gestational weeks had revealed increased nuchal thickness (9.0 mm), enhanced echos of bilateral renal parenchyma, seroperitoneum, left pleural effusion and right displacement of the heart. The mother had a previous history of terminated pregnancy for multiple fetal anomalies. No abnormality was found by conventional karyotyping and CNV analysis, though WES revealed that the fetus has harbored a de novo heterozygous c.607C>T (p.Arg203Trp) variant of the ACS1 gene (NM_018026.3), and the result was validated by Sanger sequencing.@*CONCLUSION@#Through WES and prenatal ultrasonography, the fetus was diagnosed with Schuurs-Hoeijmakers syndrome due to the heterozygous c.607C>T (p.Arg203Trp) variant of the PACS1 gene (NM_018026.3). For fetuses with multiple malformations, WES can help to reveal the genetic etiology when CNV result is negative.

Analysis of a fetus with multiple malformations due to a hemizygous variant of FANCB gene / 中华医学遗传学杂志

OBJECTIVE@#To explore the genetic basis for a fetus with limb abnormality and cardiac malformation.@*METHODS@#Clinical data of a fetus diagnosed at the Shandong Provincial Maternal and Child Health Care Hospital on April 30th, 2021 was collected. Whole exome sequencing (WES) was carried out, and candidate variant was verified by Sanger sequencing and bioinformatic analysis. X-inactivation analysis was carried out for the female members of its family.@*RESULTS@#The fetus was found to have meningoencephalocele, absence of bilateral radii, cleft lip, abnormal great arteries, and single umbilical artery at the gestational age of 11+ weeks. Sequencing revealed that the fetus has harbored a hemizygous c.1162del (p.Y388Tfs*7) variant of the FANCB gene, which was maternally inherited. Based on the guidelines from the American College of Medical Genetics and Genomics (ACMG) and ClinGen, the variant was classified as pathogenic (PVS1+PM2_Supporting+PP4). X-inactivation analysis has revealed complete skewed X-inactivation in the pregnant woman and her mother.@*CONCLUSION@#The hemizygous c.1162del (p.Y388Tfs*7) variant of the FANCB gene probably underlay the multiple malformations in this fetus.

A case of early onset diabetes with myotonic dystrophy type 1 / 中南大学学报(医学版)

Myotonic dystrophy type 1 (DM1, OMIM 160900) is a rare autosomal dominant hereditary disease. A case of DM1 patient with early onset diabetes and decreased muscle strength was treated in the Department of Endocrinology, Third Xiangya Hospital, Central South University. The peripheral blood of the patient was collected to extract DNA for gene detection. It was found that the triple nucleotide CTG repeat in the 3'-untranslated region (3'-UTR) of the dystrophia myotonica protein kinase (DMPK) gene was more than 100 times, and the diagnosis of DM1 was clear. For diabetes patients with multiple system abnormalities such as muscle symptoms, attention should be paid to the screening of DM1, a rare disease.

Clinical and genetic analyses of Joubert syndrome in children / 中国当代儿科杂志

OBJECTIVES@#To study the clinical and genetic features of Joubert syndrome (JS) in children.@*METHODS@#A retrospective analysis was performed on the clinical data, genetic data, and follow-up data of 20 children who were diagnosed with JS in the Department of Children's Rehabilitation, the Third Affiliated Hospital of Zhengzhou University, from January 2017 to July 2022.@*RESULTS@#Among the 20 children with JS, there were 11 boys and 9 girls. The common clinical manifestations were developmental delay (20 children, 100%), abnormal eye movement (19 children, 95%), and hypotonia (16 children, 80%), followed by abnormal respiratory rhythm in 5 children (25%) and unusual facies (including prominent forehead, low-set ears, and triangular mouth) in 3 children (15%), and no limb deformity was observed. All 20 children (100%) had the typical "molar tooth sign" and "midline cleft syndrome" on head images, and 6 children (30%) had abnormal eye examination results. Genetic testing was performed on 7 children and revealed 6 pathogenic genes, i.e., the CPLANE1, RPGRIP1L, MKS1, CC2D2A, CEP120, and AHI1 genes.@*CONCLUSIONS@#For children with developmental delay, especially those with abnormal eye movement and hypotonia, it is recommended to perform a head imaging examination to determine the presence or absence of "molar tooth sign" and "midline cleft syndrome", so as to screen for JS to avoid missed diagnosis and misdiagnosis. There are many pathogenic genes for JS, and whole-exome sequencing can assist in the diagnosis of JS.

Analysis of genetic variants and clinical manifestations of two children with Kabuki syndrome / 中华医学遗传学杂志

OBJECTIVE@#To report on two children with Kabuki syndrome due to variants of the KMT2D gene and summarize their clinical and genetic characteristics.@*METHODS@#Two children who had presented at the Ningbo Women and Children's Hospital respectively on August 19 and November 10, 2021 were selected as the study subjects. Clinical data were collected. Both children were subjected to whole exome sequencing (WES), and candidate variants were validated by Sanger sequencing.@*RESULTS@#Both children had featured motor and language developmental delay, facial dysmorphism and mental retardation. Genetic testing revealed that both had harbored de novo heterozygous variants of the KMT2D gene, namely c.10205del (p.Leu3402Argfs*3) and c.5104C>T (p.Arg1702*), both of which were rated as pathogenic variants based on the guidelines from the American College of Medical Genetics and Genomics (ACMG).@*CONCLUSION@#The c.10205del (p.Leu3402Argfs*3) and c.5104C>T (p.Arg1702*) variants of the KMT2D gene probably underlay the pathogenesis in these two children. Above finding has not only provided a basis for their diagnosis and genetic counseling, but also enriched the spectrum of KMT2D gene variants.

Analysis of a case of Multiple pterygium syndrome due to a novel variant of CHRNG gene / 中华医学遗传学杂志

OBJECTIVE@#To explore the clinical characteristics and genetic etiology of a child with multiple pterygium syndrome (MPS).@*METHODS@#A child with MPS who was treated at the Orthopedics Department of Guangzhou Women and Children's Medical Center Affiliated to Guangzhou Medical University on August 19, 2020 was selected as the study subject. Clinical data of the child was collected. Peripheral blood samples of the child and her parents were also collected. Whole exome sequencing (WES) was carried out for the child. Candidate variant was validated by Sanger sequencing of her parents and bioinformatic analysis.@*RESULTS@#The child, an 11-year-old female, had a complain of "scoliosis found 8 years before and aggravated with unequal shoulder height for 1 year". WES results revealed that she has carried a homozygous c.55+1G>C splice variant of the CHRNG gene, for which both of her parents were heterozygous carriers. By bioinformatic analysis, the c.55+1G>C variant has not been recorded by the CNKI, Wanfang data knowledge service platform and HGMG databases. Analysis with Multain online software suggested that the amino acid encoded by this site is highly conserved among various species. As predicted with the CRYP-SKIP online software, the probability of activation and skipping of the potential splice site in exon 1 caused by this variant is 0.30 and 0.70, respectively. The child was diagnosed with MPS.@*CONCLUSION@#The CHRNG gene c.55+1G>C variant probably underlay the MPS in this patient.

Clinical characteristics and genetic analysis of a fetus with Melnick-Needles syndrome due to variant of FLNA gene / 中华医学遗传学杂志

OBJECTIVE@#To explore the clinical and genetic characteristics of a fetus with Melnick-Needles syndrome (MNS).@*METHODS@#A fetus with MNS diagnosed at Ningbo Women and Children's Hospital in November 2020 was selected as the study subject. Clinical data was collected. Pathogenic variant was screened by using trio-whole exome sequencing (trio-WES). Candidate variant was verified by Sanger sequencing.@*RESULTS@#Prenatal ultrasonography of the fetus had shown multiple anomalies including intrauterine growth retardation, bilateral femur curvature, omphalocele, single umbilical artery, and oligohydramnios. Trio-WES revealed that the fetus has harbored hemizygous c.3562G>A (p.A1188T) missense variant of the FLNA gene. Sanger sequencing confirmed that the variant was maternally derived, whilst its father was of a wild type. Based on the guidelines from the American College of Medical Genetics and Genomics (ACMG), the variant was predicted to be likely pathogenic (PS4+PM2_Supporting+PP3+PP4).@*CONCLUSION@#The hemizygous c.3562G>A (p.A1188T) variant of the FLNA gene probably underlay the structural abnormalities in this fetus. Genetic testing can facilitate accurate diagnosis of MNS and provide a basis for genetic counseling for this family.

Genetic analysis of a child patient with rare fibrochondrogenesis due to COL11A1 gene variant / 中华医学遗传学杂志

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.

Oculo-facio-cardio-dental syndrome caused by BCOR gene mutations: a case report / 中国当代儿科杂志

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.

Clinical phenotype and genetic analysis of a child with 3p26.3p25.3 deletion / 中华医学遗传学杂志

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.

Analysis of clinical features and genetic variant in a neonate with Au-Kline syndrome due to a de novo variant of the HNRNPK gene / 中华医学遗传学杂志

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.

Clinical features and genetic analysis of a case of Wiedemann-Steiner syndrome due to variant of KMT2A gene / 中华医学遗传学杂志

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.

Clinical features and genetic analysis of two Chinese pedigrees affected with Joubert syndrome / 中华医学遗传学杂志

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.