Clinical and genetic analysis of a Chinese pedigree affected with MRXS34 syndrome due to variant of NONO gene

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ACMG SF v3.0 list for reporting of secondary findings in clinical exome and genome sequencing: a policy statement of the American College of Medical Genetics and Genomics (ACMG)

Updated recommendations for CFTR carrier screening: A position statement of the American College of Medical Genetics and Genomics (ACMG)

The use of ACMG secondary findings recommendations for general population screening: a policy statement of the American College of Medical Genetics and Genomics (ACMG)

To explore the genetic etiology of a child with Renpenning syndrome (RS), and review the literature on the clinical characteristics and gene mutations of RS. A child with RS (patient 1) who was diagnosed and treated in the Pediatric Intensive Care Unit of the Third Affiliated Hospital of Zhengzhou University in November 2023 was selected as the research object. The medical history, family history, physical examination, cerebrospinal fluid examination, echocardiography, brain magnetic resonance imaging (MRI), brain magnetic resonance angiography, cardiac coronary CT angiography and intelligence quotient (IQ) score of child 1 were retrospectively collected. Peripheral venous blood samples were collected from patient 1, his parents, sister and brother, respectively. Genomic DNA was extracted from the child and his family members, and Trios-whole exome sequencing (Trios-WES) was performed. Sanger sequencing was used to verify the pedigree. Bioinformatics softwares (Mutation Taster, REVEL, SIFT, PolyPhen-2, GERP++, SWISS-MODEL) were applied. The pathogenicity of the detected variants was rated according to the American College of Medical Genetics and Genomics (ACMG) Standards and Guidelines for the Classification of Genetic Variants (hereinafter referred to as the ACMG Guidelines). "PQBP1 gene" "Renpenning syndrome" "PQBP1 gene" "Renpenning syndrome" were used as keywords in Chinese and English, respectively. Case reports of patients with RS caused by PQBP1 gene variants were retrieved from Wanfang Data Knowledge Service Platform, China National Knowledge Infrastructure and PubMed database. The clinical features and gene variants of RS caused by PQBP1 gene variants were summarized and analyzed. This study was reviewed by the Medical Ethics Committee of the Third Affiliated Hospital of Zhengzhou University (Approval No. 2024-334-01). The patient 1, a 12-year-old boy, was admitted to the hospital due to fever and disturbance of consciousness. Cerebrospinal fluid test showed viral encephalitis caused by human herpesvirus 7 infection. The main clinical manifestations were unusual facies (microcephaly, long narrow face, microphthalmos, superior oblique palpebral fissure, hypertelorism of inner canthus, bulbous nasal columella) and mental retardation. Auxiliary examination showed than patient 1 had atrial septal defect, nodular heterotopia in the posterior horn of the left ventricle, angiodysplasia, and low IQ. The disease began in infancy, and there was no family history of related diseases. A hemizygous deletion, c.459_462del (p.Arg153SerfsTer41), was identified in exon 5 of the PQBP1 gene in patient 1, which was inherited from his mother by Sanger sequencing. The results of bioinformatics analysis showed that the mutation was harmful. This variant was rated as pathogenic (PVS1+PS4+PM2_Supporting+PP3) according to ACMG Guidelines. According to the literature search strategy set in this study, a total of 13 cases of RS were retrieved, involving 16 cases of RS patient caused by PQBP1 gene mutation (patients 2-17), including patient 1, a total of 17 cases of RS. Among the 17 patients, 16 male patients had hemizygous mutations in the X chromosome PQBP1 gene, and 1 female patient had heterozygous mutations, including 12 deletion frameshift nonsense mutations, 3 point missense mutations, and 2 duplication mutations. Except for two fetuses, all patients had special facial features and low IQ to varying degrees. Ten patients had abnormal development of one or more organs such as eyes, heart, brain, etc. CONCLUSION: The main clinical manifestations of RS are developmental delay, long narrow face, bulbous nose, microcephaly, and may be accompanied by heterotopia of gray matter of ventricle and congenital heart disease. The c.459_462del (p.Arg153SerfsTer41) variant of the PQBP1 gene is the genetic basis of patient 1 in this study.

Tetrasomy of 11q13.4-q14.3 due to an intrachromosomal triplication associated with paternal uniparental isodisomy for 11q14.3-qter, intrauterine growth restriction, developmental delay, corpus callosum dysgenesis, microcephaly, congenital heart defects and facial dysmorphism

Does the law require reinterpretation and return of revised genomic results?

Exome and genome sequencing for pediatric patients with congenital anomalies or intellectual disability: an evidence-based clinical guideline of the American College of Medical Genetics and Genomics (ACMG)

To analyze the clinical manifestations and genotype of a child with You-Hoover-Fong syndrome (YHFS) to enhance clinical understanding of this disease. Clinical data of a child who visited the Department of Pediatric Neurorehabilitation of the Women's and Children's Hospital Affiliated to Xiamen University in March 2025 for global developmental delay was collected. Peripheral blood samples of the child and his parents were collected for chromosomal microarray analysis and whole exome sequencing (WES). Sanger sequencing was performed for parental validation, and candidate variant was assessed for pathogenicity. Clinical and genetic analyses were conducted based on the child's phenotype. A literature review was performed by retrieving previously reported cases of YHFS due to TELO2 gene variants. This study was approved by the Medical Ethics Committee of the Women's and Children's Hospital Affiliated to Xiamen University (Ethics No.: KY-2023-044-K02). The child was a 1-year-and-2-month-old male presenting with global developmental delay, encephalodysplasia, congenital heart disease and distinctive facial features. WES revealed that the child has harbored compound heterozygous variants of the TELO2 gene, namely c.1826G>A (p.Arg609His) and c.1514_1515delAG (p.Glu505Alafs21). Sanger sequencing confirmed that his mother carried a heterozygous c.1826G>A variant and his father carried a heterozygous c.1514_1515delAG variant. Based on the guidelines from the American College of Medical Genetics and Genomics (ACMG), both variants were classified as likely pathogenic (PM2_Supproting+PM3_Strong+PP1+PP3; PVS1+PM2_Supproting). Literature review has identified 9 articles reporting 31 cases of YHFS due to TELO2 gene variants, with primary clinical manifestations including developmental delay, intellectual disability, distinctive facial features, and congenital heart disease. The c.1826G>A (p.Arg609His) and c.1514_1515delAG (p.Glu505Alafs*21) compound heterozygous variants of the TELO2 gene probably underlay the pathogenesis of this child. Above finding has provided a basis for the clinical and genetic diagnosis of the child, which also enriched the mutational spectrum of the TELO2 gene, and improved understanding of YHFS.

To explore the clinical phenotype and genetic etiology of a fetus with autosomal dominant intellectual disability type 72 (MRD72) resulting from a variant of the SRRM2 gene. A Chinese pedigree with MRD72 (fetus) who had visited the Affiliated Women and Children's Hospital of Ningbo University in November 2024 was selected as study subject. Clinical data of the pedigree were collected. Amniotic fluid and peripheral blood samples were collected from the fetus and its parents for genomic DNA extraction. Whole-exome sequencing (WES) was carried out, and candidate variants were verified by Sanger sequencing of the family members and rated based on guidelines from the American College of Medical Genetics and Genomics (ACMG). Relevant literature on MRD72 were searched in domestic and international databases for a review. This study was approved by the hospital (Ethics No.: EC2023-094). The proband was a fetus of 25 weeks of gestation. Fetal echocardiography revealed a relatively small left atrium and left ventricle, along with a diminished aortic-to-pulmonary artery ratio. WES revealed that the fetus has harbored a heterozygous nonsense variant of the SRRM2 gene. Sanger sequencing confirmed both parents carried the wild-type alleles. Based on guidelines from the American College of Medical Genetics and Genomics (ACMG), the variant was rated as likely pathogenic (PVS1+PM2_Supporting) and has not been recorded in public databases. Bioinformatic analysis predicted amino acid 512 to be highly conserved across various species. According to the pre-set literature search strategy, 4 publications were retrieved, which involved 30 MRD72 patients from 27 pedigrees, In addition to this study, a total of 31 cases were included. Analysis of clinical features and genetic etiology showed that patients with MRD72 presented mainly with clinical manifestations such as mental and motor development delay, special facial features, speech/intellectual development delay, and obesity. The genetic etiology was all variants at relevant loci of the SRRM2 gene. The SRRM2 variant identified in this study is implicated as the genetic cause of MRD72 in the proband. Above results have expanded the mutational and phenotypic spectra of the SRRM2 gene.

eP344: Making the grade: How carrier screening panels score against the American College of Medical Genetics and Genomics “Tier 3” recommendations

Genetics in Medicine Open to us all

To explore the genetic etiology for a child presenting with motor retardation, language delay, intellectual disability, and dysmorphic features. A child presented at Linyi People's Hospital in June 2022 was selected as the study subject. Clinical data of the child was collected. Peripheral blood samples were obtained from the child and her parents. Following extraction of genomic DNA, whole-exome sequencing (WES) was carried out. Candidate variant was validated by Sanger sequencing. Amniotic fluid samples were obtained from the mother's subsequent pregnancies for prenatal diagnosis. This study has been reviewed and approved by the Medical Ethics Committee of Linyi People's Hospital (Ethics No.: 2019-134). The proband was a 2-year-old girl showing developmental delays in motor, language, and intellectual domains, strabismus, hypertelorism, hearing impairment, obesity, and brachymesophalangy of the fifth finger. Magnetic resonance imaging revealed abnormalities of the white matter. Chromosomal microarray analysis (CMA) identified a 15q26.3 duplication (chr15:101562020_102060896 × 3) inherited from her mother. WES has uncovered a heterozygous c.1931A>G (p.Tyr644Cys) variant in the FBXO11 gene. Sanger sequencing confirmed the variant to be de novo in origin. Based on the guidelines from the American College of Medical Genetics and Genomics (ACMG), the variant was classified as likely pathogenic. Prenatal diagnosis revealed that the fetuses from the mother's second and third pregnancies did not harbor the same variant. The c.1931A>G (p.Tyr644Cys) variant of the FBXO11 gene probably underlay the abnormal phenotype in the child. Based on its genotype and phenotype, the proband was diagnosed with Intellectual developmental disorder with dysmorphic facies and behavioral abnormalities.

To explore the genetic etiology of two patients with developmental delay and intellectual disability. Two children who were respectively admitted to Henan Provincial People's Hospital on August 29, 2021 and August 5, 2019 were selected as the study subjects. Clinical data were collected, and array comparative genomic hybridization (aCGH) was carried out on the children and their parents for the detection of chromosomal microduplication/microdeletions. Patient 1 was a 2-year-and-10-month female and patient 2 was a 3-year-old female. Both children had featured developmental delay, intellectual disability, and abnormal findings on cranial MRI. aCGH revealed that patient 1 has harbored arr[hg19] 6q14.2q15(84621837_90815662)×1, a 6.19 Mb deletion at 6q14.2q15, which encompassed ZNF292, the pathogenic gene for Autosomal dominant intellectual developmental disorder 64. Patient 2 has harbored arr[hg19] 22q13.31q13.33(46294326_51178264)×1, a 4.88 Mb deletion at 22q13.31q13.33 encompassing the SHANK3 gene, haploinsufficiency of which can lead to Phelan-McDermid syndrome. Both deletions were classified as pathogenic CNVs based on the guidelines of American College of Medical Genetics and Genomics (ACMG) and were not found in their parents. The 6q14.2q15 deletion and 22q13-31q13.33 deletion probably underlay the developmental delay and intellectual disability in the two children, respectively. Haploinsufficiency of the ZNF292 gene may account for the key clinical features of the 6q14.2q15 deletion.

To analyze the clinical phenotype and genetic etiology of patients with Dyggve-Melchior-Clausen syndrome (DMC syndrome). A child with DMC syndrome diagnosed at Shanghai Children's Medical Center, School of Medicine, Shanghai Jiao Tong University in August 2020 was selected as study subject. A retrospective analysis was carried out to collect the proband's clinical data. Peripheral blood samples was collected from the proband and his parents. Following extraction of genomic DNA, whole exome sequencing (WES) was carried out. Candidate variants were validated within the family by Sanger sequencing. Pathogenicity of candidate variants was rated based on guidelines from the American College of Medical Genetics and Genomics (ACMG). This study was approved by the Medical Ethics Committee of the center (Ethics No.: SCMCIRB-K2023024-1). The proband, a 5-year-and-7-month-old girl, presented with short stature (height: -5.5 s) and intellectual disability. Physical examination revealed microcephaly (head circumference: -3.5 s), coarse facial features, long philtrum, pigeon chest, and brachydactyly of both hands. Laboratory findings revealed normal serum insulin-like growth factor-1 (IGF-1) levels (168 ng/mL). Imaging analysis demonstrated dysplasia of corpus callosum and spondyloepiphyseal dysplasia in the proband. WES revealed that she has harbored compound heterozygous variants of the DYM gene, namely c.312-313del (p.His104Glnfs*29) and c.1274A>T (p.Tyr425Phe). Both variants were unreported previously and inherited from her parents who were phenotypically normal. Based on guidelines from the ACMG, the DYM gene variant c.312-313del (p.His104Glnfs*29) was classified as pathogenic (PVS1+PM2_Supporting+PP3+PP4_supporting), while the c.1274A>T (p.Tyr425Phe) variant was classified as likely pathogenic (PM2_Supporting+PP3+PP1+PP4_supporting). By following the pre-set literature search strategy, a total of 20 articles were included, which involved a total of 73 cases of DYM gene variants leading to DMC syndrome. Among these, only one family case was documented in China. Together with proband from this study, a total of 74 DMC syndrome patients due DYM gene variants were included for a comprehensive analysis of clinical phenotypes and genetic characteristics. The age at the time of reporting ranged from 1 to 60 years. The main clinical manifestations included intellectual disability, short stature, and spondyloepiphyseal dysplasia, followed by microcephaly and coarse facial features. By genetic testing, c.1877delA variant was the most common mutation at the nucleotide level. The c.312-313del/c.1274A>T compound heterozygous variants of the DYM gene probably underlay the pathogenesis of DMC syndrome in this proband. Above finding has expanded the mutational and phenotypic spectra of the DMC syndrome.