RESUMEN
Not required for Clinical Vignette.
Asunto(s)
Hormona de Crecimiento Humana , Micrognatismo , Humanos , Hormona de Crecimiento Humana/uso terapéutico , Masculino , Micrognatismo/tratamiento farmacológico , Deformidades Congénitas de la Mano/tratamiento farmacológico , Deformidades Congénitas de la Mano/genética , Resultado del Tratamiento , Anomalías Múltiples/tratamiento farmacológico , Anomalías Múltiples/genética , Discapacidad Intelectual/tratamiento farmacológico , Cuello/anomalías , Cara/anomalías , Proteínas Recombinantes/uso terapéuticoRESUMEN
BACKGROUND: Contiguous gene deletion in the short arm of chromosome 4 is linked to various neurodevelopmental disorders. METHODS: In this study, we conducted peripheral blood chromosome G-banding karyotyping and whole-exome sequencing (WES) on a proband presenting with anal atresia, global developmental delay, lymphocytosis, and other multisystem anomalies. Additionally, chromosome G-banding karyotyping was also carried out on the proband's parents and brother. RESULTS: The 7-month-old proband was found to have a 26.738 Mb 4p15.33-p14 deletion as identified by chromosome G-banding karyotyping and WES. CONCLUSION: We identified a patient with proximal 4p deletion syndrome by karyotype and WES analysis, which might explain some of his phenotypes. Our research enhances clinicians' knowledge of this rare condition, and offers valuable genetic counseling to the affected family. Further research is necessary to identify the causative gene or critical region associated with proximal 4p deletion syndrome.
Asunto(s)
Anomalías Múltiples , Deleción Cromosómica , Cromosomas Humanos Par 4 , Humanos , Masculino , Lactante , Anomalías Múltiples/genética , Anomalías Múltiples/patología , Cromosomas Humanos Par 4/genética , Fenotipo , Trastornos de los Cromosomas/genética , Trastornos de los Cromosomas/patología , Cariotipificación , Secuenciación del ExomaRESUMEN
Genetic variants in the zone of polarizing activity regulatory sequence (ZRS) that induce ectopic expression of the SHH gene have been associated with different ZRS-related phenotypes. We report the first patient with a de novo variant, c.423+4916 T>C, in ZRS (previously classified as a variant of uncertain significance) that causes tibial hemimelia-polysyndactyly-triphalangeal thumb syndrome (THPTTS). A two-month-old male patient presented with bilateral preaxial polydactyly, triphalangeal thumb, and tibial agenesis and was heterozygous for the variant c.423+4916T>C (neither of his parents was a carrier). The findings obtained from the family study were sufficient to reclassify the variant from "uncertain significance" to "likely pathogenic" according to three criteria from the American College of Medical Genetics and Genomics guidelines, as follows: (1) absence of gnomAD, (2) confirmation of paternity and maternity, and (3) strong phenotype-genotype association. In ZRS-associated syndromes, a wide clinical spectrum has been observed, ranging from polydactyly to THPTTS; our patient has the most severe and rare phenotype. We did not perform functional assays. However, the c.423+4916T>C variant is flanked by three variants, which have been proven not only to cause the phenotype but also to increase the expression of SHH. Through all this data gathering, we consider the c.423+4916T>C variant to be causative of THPTTS.
Asunto(s)
Pulgar , Humanos , Masculino , Pulgar/anomalías , Lactante , Tibia/anomalías , Polidactilia/genética , Fenotipo , Ectromelia/genética , Proteínas Hedgehog/genética , Dedos/anomalías , Anomalías Múltiples/genética , Deformidades Congénitas de la Mano/genética , Dedos del Pie/anomalías , Mutación , Estudios de Asociación Genética , Anomalías Congénitas , Disostosis MandibulofacialAsunto(s)
Cromosomas Humanos Par 9 , Segundo Trimestre del Embarazo , Ultrasonografía Prenatal , Humanos , Femenino , Embarazo , Ultrasonografía Prenatal/métodos , Cromosomas Humanos Par 9/genética , Adulto , Anomalías Múltiples/genética , Anomalías Múltiples/diagnóstico por imagen , Análisis por Micromatrices/métodos , Reacción en Cadena de la Polimerasa/métodos , Aneuploidia , Aberraciones Cromosómicas/embriologíaRESUMEN
OBJECTIVE: To analyze the lymphocyte subsets in individuals with Kabuki syndrome for better characterizing the immunological phenotype of this rare congenital disorder. METHODS: We characterized the immunological profile including B-, T- and natural killer-cell subsets in a series (N = 18) of individuals with Kabuki syndrome. RESULTS: All 18 individuals underwent genetic analysis: 15 had a variant in KMT2D and 3 a variant in KDM6A. Eleven of the 18 individuals (61%) had recurrent infections and 9 (50%) respiratory infections. Three (17%) had autoimmune diseases. On immunological analysis, 6 (33%) had CD4 T-cell lymphopenia, which was preferentially associated with the KMT2D truncating variant (5/9 individuals). Eight of 18 individuals (44%) had a humoral deficiency and eight (44%) had B lymphopenia. We found abnormal distributions of T-cell subsets, especially a frequent decrease in recent thymic emigrant CD4 + naive T-cell count in 13/16 individuals (81%). CONCLUSION: The immunological features of Kabuki syndrome showed variable immune disorders with CD4 + T-cell deficiency in one third of cases, which had not been previously reported. In particular, we found a reduction in recent thymic emigrant naïve CD4 + T-cell count in 13 of 16 individuals, representing a novel finding that had not previously been reported.
Asunto(s)
Anomalías Múltiples , Proteínas de Unión al ADN , Cara , Histona Demetilasas , Proteínas de Neoplasias , Enfermedades Vestibulares , Humanos , Enfermedades Vestibulares/genética , Enfermedades Vestibulares/inmunología , Cara/anomalías , Femenino , Masculino , Anomalías Múltiples/genética , Anomalías Múltiples/inmunología , Niño , Proteínas de Unión al ADN/genética , Adolescente , Histona Demetilasas/genética , Preescolar , Adulto , Proteínas de Neoplasias/genética , Proteínas de Neoplasias/inmunología , Adulto Joven , Lactante , Linfopenia/inmunología , Linfopenia/genética , Fenotipo , Enfermedades Hematológicas/genética , Enfermedades Hematológicas/inmunología , Mutación , Subgrupos Linfocitarios/inmunología , Subgrupos Linfocitarios/metabolismo , InmunofenotipificaciónRESUMEN
BACKGROUND: Kagami-Ogata syndrome (KOS) and Temple syndrome (TS) are two imprinting disorders characterized by the absence or reduced expression of maternal or paternal genes in the chromosome 14q32 region, respectively. We present a rare prenatally diagnosed case of recurrent KOS inherited from a mother affected by TS. CASE PRESENTATION: The woman's two affected pregnancies exhibited recurrent manifestations of prenatal overgrowth, polyhydramnios, and omphalocele, as well as a small bell-shaped thorax with coat-hanger ribs postnatally. Prenatal genetic testing using a single-nucleotide polymorphism array detected a 268.2-kb deletion in the chromosome 14q32 imprinted region inherited from the mother, leading to the diagnosis of KOS. Additionally, the woman carried a de novo deletion in the paternal chromosome 14q32 imprinted region and presented with short stature and small hands and feet, indicating a diagnosis of TS. CONCLUSIONS: Given the rarity of KOS as an imprinting disorder, accurate prenatal diagnosis of this rare imprinting disorder depends on two factors: (1) increasing clinician recognition of the clinical phenotype and related genetic mechanism, and (2) emphasizing the importance of imprinted regions in the CMA workflow for laboratory analysis.
Asunto(s)
Diagnóstico Prenatal , Humanos , Femenino , Embarazo , Adulto , Impresión Genómica , Cromosomas Humanos Par 14/genética , Anomalías Múltiples/genética , Anomalías Múltiples/diagnóstico , Polimorfismo de Nucleótido Simple , Trastornos de Impronta , Pulgar/anomalías , Hipotonía Muscular , Discapacidad Intelectual , Facies , Uñas Malformadas , Hallux/anomalíasRESUMEN
Takenouchi-Kosaki syndrome (TKS) is a rare congenital disease caused by a de novo mutation in the Cell Division Cycle 42 (CDC42) gene. Patients with TKS present facial and body dysmorphisms, hematologic and immune dysregulation, intellectual disability, neurodevelopmental delay and hearing loss. The aim of this study is to review the literature, focusing on hearing and language abilities in children with TKS. A systematic search on PubMed, Scopus and Web of Science databases was performed, including twelve studies for a total of 13 patients. Hearing loss (HL) occurs in a great percentage of patients (84.6%); nonetheless, auditory threshold, severity of HL and language abilities were reported in a few cases. In two studies, auditory rehabilitation strategies were described. Although several studies have investigated the hematological features of TKS, still only a few authors have focused on the audiological and language abilities of these children. Given the fact that HL has a significant impact on behaviors, communications skills, and quality of life, it is important to adequately assess and rehabilitate patients early with this syndrome. Further studies are needed to improve the knowledge about this topic and improve the quality of life of patients with TKS.
Asunto(s)
Pérdida Auditiva , Humanos , Niño , Pérdida Auditiva/genética , Calidad de Vida , Anomalías Múltiples/genética , Preescolar , Desarrollo del LenguajeRESUMEN
BACKGROUND: Feeding difficulties frequently co-occur with multisystem disorders attributed to rare genetic diseases. In this study, we aimed to describe the genetic manifestations and phenotype spectrum in infants experiencing feeding difficulties. METHODS: This case series included infants under 6 months old with feeding difficulties admitted to the neonatal department of Children's Hospital, Zhejiang University School of Medicine from October 2018 to May 2022. All infants underwent whole-exome sequencing (WES) during hospitalisation, and their clinical phenotypes and genetic results were analyzed. RESULTS: Among 28 infants studied, nine were preterm and 19 were full-term. Median admission age was 13.5 days (IQR 6.5, 35), with a median hospital stay of 16 days (IQR 10.5, 30). Overall, 12 (42.9%) cases were complicated with multiple malformations. Abnormal muscle tone (53.6%) and neurological issues (42.9%) were notable prevalent in these infants. Cranial MR abnormalities were noted in 96.2% of cases. Based on the combined analysis of WES results and clinical phenotypes, a total of 22 (78.3%) patients displayed disease-related genetic variation identified through WES; among them, 15 (53.6%) patients received genetic diagnoses, while 7 (25%) patients were suspected diagnoses. Positive findings were more frequent in full-term (89.5%) than preterm infants (55.6%). Ultimately, 24 (85.7%) patients were discharged alive, with 75% requiring post-discharge tube feeding. Following discharge, five patients developed new symptoms linked to genetic variants, and two patients died. CONCLUSIONS: Feeding difficulty may constitute a facet of the phenotypic spectrum of rare genetic diseases. Whole-exome sequencing can enhance molecular diagnosis accuracy for infants with feeding difficulties.
Asunto(s)
Secuenciación del Exoma , Fenotipo , Humanos , Masculino , Femenino , Lactante , Recién Nacido , Anomalías Múltiples/genética , Anomalías Múltiples/patologíaRESUMEN
BACKGROUND: Biallelic SUFU variants have originally been linked to Joubert syndrome, comprising cerebellar abnormalities, dysmorphism, and polydactyly. In contrast, heterozygous truncating variants have recently been associated with developmental delay and ocular motor apraxia, but only a limited number of patients have been reported. Here, we aim to delineate further the mild end of the phenotypic spectrum related to SUFU haploinsufficiency. METHODS: Nine individuals (from three unrelated families) harboring truncating SUFU variants were investigated, including two previously reported individuals (from one family). We provide results from a comprehensive assessment comprising neuroimaging, neuropsychology, video-oculography, and genetic testing. RESULTS: We identified three inherited or de novo truncating variants in SUFU (NM_016169.4): c.895C>T p.(Arg299∗), c.71dup p.(Ala25Glyfs∗23), and c.71del p.(Pro24Argfs∗72). The phenotypic expression showed high variability both between and within families. Clinical features include motor developmental delay (seven of nine), axial hypotonia (five of nine), ocular motor apraxia (three of nine), and cerebellar signs (three of nine). Four of the six reported children had macrocephaly. Neuropsychological and developmental assessments revealed mildly delayed language development in the youngest children, whereas general cognition was normal in all variant carriers. Subtle but characteristic SUFU-related neuroimaging abnormalities (including superior cerebellar dysplasia, abnormalities of the superior cerebellar peduncles, rostrally displaced fastigium, and vermis hypoplasia) were observed in seven of nine individuals. CONCLUSIONS: Our data shed further light on the mild but recognizable features of SUFU haploinsufficiency and underline its marked phenotypic variability, even within families. Notably, neurodevelopmental and behavioral abnormalities are mild compared with Joubert syndrome and seem to be well compensated over time.
Asunto(s)
Discapacidades del Desarrollo , Haploinsuficiencia , Fenotipo , Humanos , Masculino , Femenino , Niño , Preescolar , Discapacidades del Desarrollo/diagnóstico por imagen , Discapacidades del Desarrollo/genética , Discapacidades del Desarrollo/etiología , Discapacidades del Desarrollo/fisiopatología , Adolescente , Cerebelo/diagnóstico por imagen , Cerebelo/anomalías , Apraxias/diagnóstico por imagen , Apraxias/genética , Apraxias/fisiopatología , Apraxias/congénito , Enfermedades Renales Quísticas/genética , Enfermedades Renales Quísticas/diagnóstico por imagen , Anomalías Múltiples/genética , Anomalías Múltiples/diagnóstico por imagen , Anomalías Múltiples/fisiopatología , Neuroimagen , Anomalías del Ojo/genética , Anomalías del Ojo/diagnóstico por imagen , Retina/diagnóstico por imagen , Retina/anomalías , Síndrome de CoganRESUMEN
BACKGROUND: The MACF1 gene, found on chromosome 1p34.3, is vital for controlling cytoskeleton dynamics, cell movement, growth, and differentiation. It consists of 101 exons, spanning over 270 kb. The 16p13.11 microduplication syndrome results from the duplication of 16p13.11 chromosome copies and is associated with various neurodevelopmental and physiological abnormalities. Both MACF1 and 16p13.11 microduplication have significant impacts on neural development, potentially leading to nerve damage or neurological diseases. This study presents a unique case of a patient simultaneously experiencing a de novo MACF1 mutation and a hereditary 16p13.11 microduplication, which has not been reported previously. CASE PRESENTATION: In this report, we describe a Chinese preterm newborn girl exhibiting the typical characteristics of 16.13.11 microduplication syndrome. These features include developmental delay, respiratory issues, feeding problems, muscle weakness, excessive joint movement, and multiple congenital abnormalities. Through whole-exome sequencing, we identified a disease-causing mutation in the MACF1 gene (c.15266T > C / p. Met5089Thr). Additionally, after microarray analysis, we confirmed the presence of a 16p13.11 microduplication (chr16:14,916,289 - 16,315,688), which was inherited from the mother. CONCLUSIONS: The patient's clinical presentation, marked by muscle weakness and multiple birth defects, may be attributed to both the de novo MACF1 mutation and the 16p13.11 duplication, which could have further amplified her severe symptoms. Genetic testing for individuals with complex clinical manifestations can offer valuable insights for diagnosis and serve as a reference for genetic counseling for both patients and their families.
Asunto(s)
Anomalías Múltiples , Cromosomas Humanos Par 16 , Hipotonía Muscular , Humanos , Femenino , Recién Nacido , Hipotonía Muscular/genética , Cromosomas Humanos Par 16/genética , Anomalías Múltiples/genética , Recien Nacido Prematuro , Duplicación Cromosómica , Mutación , Proteínas de Microfilamentos/genéticaRESUMEN
The term "recurrent constellations of embryonic malformations" (RCEM) is used to describe a number of multiple malformation associations that affect three or more body structures. The causes of these disorders are currently unknown, and no diagnostic marker has been identified. Consequently, providing a definitive diagnosis in suspected individuals is challenging. In this study, genome-wide DNA methylation analysis was conducted on DNA samples obtained from the peripheral blood of 53 individuals with RCEM characterized by clinical features recognized as VACTERL and/or oculoauriculovertebral spectrum association. We identified a common DNA methylation episignature in 40 out of the 53 individuals. Subsequently, a sensitive and specific binary classifier was developed based on the DNA methylation episignature. This classifier can facilitate the use of RCEM episignature as a diagnostic biomarker in a clinical setting. The study also investigated the functional correlation of RCEM DNA methylation relative to other genetic disorders with known episignatures, highlighting the common genomic regulatory pathways involved in the pathophysiology of RCEM.
Asunto(s)
Metilación de ADN , Humanos , Femenino , Masculino , Anomalías Múltiples/genética , Deformidades Congénitas de las Extremidades/genética , Deformidades Congénitas de las Extremidades/diagnósticoRESUMEN
Zimmermann-Laband Syndrome (ZLS; MIM 135500) is a rare genetic disorder with the main clinical manifestations of gingival fibromatosis and finger/toe nail hypoplasia. KCNH1 (potassium channel, voltage-gated, subfamily H, member-1), KCNN3 (potassium channel, voltage-gated, subfamily H, member-3) and ATP6V1B2 (ATPase H+ transporting V1 subunit B2) genes are considered causative genes for ZLS. However, there are limited reports about the diverse clinical presentation and genetic heterogeneity. Reporting more information on phenotype-genotype correlation and the treatment of ZLS is necessary. This case reported a 2-year-old patient with gingival enlargement that failure of eruption of the deciduous teeth and severe hypoplasia of nails. Based on a systemic examination and a review of the relevant literature, we made an initial clinical diagnosis of ZLS. A novel pathogenic variant in the KCNH1 gene was identified using whole-exome sequencing to substantiate our preliminary diagnosis. The histopathological results were consistent with gingival fibromatosis. Gingivectomy and gingivoplasty were performed under general anesthesia. After surgery, the gingival appearance improved significantly, and the masticatory function of the teeth was restored. After 2-year follow-up, the gingival showed slightly hyperplasia. Systemic examination and gene sequencing firstly contribute to provide information for an early diagnosis for ZLS, then timely removal of the hyperplastic gingival facilitates the establishment of a normal occlusal relationship and improves oral aesthetics.
Asunto(s)
Fibromatosis Gingival , Humanos , Fibromatosis Gingival/genética , Preescolar , Deformidades Congénitas de la Mano/genética , Anomalías Múltiples/genética , Masculino , Gingivectomía/métodos , Femenino , Uñas Malformadas/genética , Anomalías CraneofacialesRESUMEN
Macrophage activation syndrome (MAS), is a severe and fatal complication of various pediatric inflammatory disorders. Kabuki syndrome (KS), mainly caused by lysine methyltransferase 2D (KMT2D; OMIM 602113) variants, is a rare congenital disorder with multi-organ deficiencies. To date, there have been no reported cases of MAS in patients with KS. This report describes a case of a 22-year-old male with Kabuki syndrome (KS) who developed MAS. This unique case not only deepens the understanding of the involvement of KMT2D in immune regulation and disease, but expands the phenotype of the adult patient to better understand the natural history, disease burden, and management of patients with KS complicated with autoimmune disorders.
Asunto(s)
Anomalías Múltiples , Cara , Enfermedades Hematológicas , Síndrome de Activación Macrofágica , Enfermedades Vestibulares , Humanos , Masculino , Enfermedades Vestibulares/etiología , Enfermedades Vestibulares/genética , Enfermedades Vestibulares/diagnóstico , Enfermedades Hematológicas/etiología , Enfermedades Hematológicas/diagnóstico , Cara/anomalías , Anomalías Múltiples/genética , Síndrome de Activación Macrofágica/diagnóstico , Síndrome de Activación Macrofágica/etiología , Adulto Joven , Proteínas de Neoplasias/genética , Fenotipo , N-Metiltransferasa de Histona-Lisina/genética , Proteínas de Unión al ADN/genéticaRESUMEN
PURPOSE: Megacystis microcolon intestinal hypoperistalsis syndrome (MMIHS) is defined as a congenital visceral myopathy with genetic mutations. However, the etiology and pathophysiology are not fully understood. We aimed to generate a gene leiomodin-1a (lmod1a) modification technique to establish a zebrafish model of MMIHS. METHODS: We targeted lmod1a in zebrafish using CRISPR/Cas9. After confirming the genotype, we measured the expression levels of the target gene and protein associated with MMIHS. A gut transit assay and spatiotemporal mapping were conducted to analyze the intestinal function. RESULTS: Genetic confirmation showed a 5-base-pair deletion in exon 1 of lmod1a, which caused a premature stop codon. We observed significant mRNA downregulation of lmod1a, myh11, myod1, and acta2 and the protein expression of Lmod1 and Acta2 in the mutant group. A functional analysis of the lmod1a mutant zebrafish showed that its intestinal peristalsis was fewer, slower, and shorter in comparison to the wild type. CONCLUSION: This study showed that targeted deletion of lmod1a in zebrafish resulted in depletion of MMIHS-related genes and proteins, resulting in intestinal hypoperistalsis. This model may have the potential to be utilized in future therapeutic approaches, such as drug discovery screening and gene repair therapy for MMIHS.
Asunto(s)
Sistemas CRISPR-Cas , Colon , Modelos Animales de Enfermedad , Seudoobstrucción Intestinal , Pez Cebra , Animales , Pez Cebra/genética , Seudoobstrucción Intestinal/genética , Colon/anomalías , Mutación , Vejiga Urinaria/anomalías , Anomalías Múltiples/genética , Proteínas Musculares/genética , Proteínas de Pez Cebra/genéticaRESUMEN
OBJECTIVE: To explore the clinical phenotype and genetic basis of a child with Bainbridge-Ropers syndrome (BRPS). METHODS: A child with BRPS who had visited Nanjing Children's Hospital on June 26, 2019 was selected as the study subject. Clinical data of the child was reviewed. Genomic DNA was extracted from peripheral blood samples of the child and her parents. Whole exome sequencing (WES) was carried out, and candidate variant was verified by Sanger sequencing and bioinformatic analysis. RESULTS: The child was a 6-month-old girl with peculiar facial features, feeding difficulties, malnutrition, global developmental delay, hypotonia, mildly elevated aminotransferase and ulnar deviation. Results of WES showed that she has harbored a c.1533_1534del variant of the ASXL3 gene. Sanger sequencing confirmed that neither of her parents has carried the same variant. No similar case had been retrieved from the HGMD and ClinVar databases. No frequency for this variant among Asian populations was available in the ExAC, 1000 Genomes, and gnomAD databases. Based on the guidelines from the American College of Medical Genetics and Genomics (ACMG), the c.1533_1534del variant of the ASXL3 gene was determined to be likely pathogenic (PVS1+PS2+PM2_Supporting). CONCLUSION: The ASXL3 gene c.1533_1534del variant probably underlay the BRPS in this child. Above finding has provided a reference for the clinical diagnosis and genetic counseling for children with similar disorders.
Asunto(s)
Anomalías Múltiples , Discapacidades del Desarrollo , Trastornos del Neurodesarrollo , Femenino , Humanos , Lactante , Anomalías Múltiples/genética , Discapacidades del Desarrollo/genética , Secuenciación del Exoma , Facies , Mutación , Trastornos del Neurodesarrollo/genética , Fenotipo , Proteínas RepresorasRESUMEN
OBJECTIVE: To explore the clinical characteristics and genetic basis for a fetus with Joubert syndrome. METHODS: A pregnant woman who had visited Suzhou Municipal Hospital on February 26, 2021 was selected as the study subject. The fetus and her parents were subjected to whole exome sequencing (WES), and candidate variants were verified by Sanger sequencing. cDNA analysis of her father and RNA sequencing of her sister were also carried out. RESULTS: The fetus was found to harbor compound heterozygous variants of the TCTN1 gene, namely c.624G>A and c.96dupA (p.Glu33Argfs*49), which were inherited from her father and mother, respectively. Her sister also carried the paternal c.624G>A variant, and mRNA transcripts with the c.624G>A variant of the TCTN1 gene were not detected by cDNA analysis of her father and RNA sequencing of her sister. Based on the guidelines from the American College of Medical Genetics and Genomics (ACMG), the c.624G>A and c.96dupA variants were both classified as likely pathogenic (PVS1+PM2_Supporting). CONCLUSION: The compound heterozygous variants of the TCTN1 gene probably underlay the pathogenesis in this fetus. Above finding has also expanded the mutational spectrum of the TCTN1 gene.
Asunto(s)
Anomalías Múltiples , Cerebelo , Anomalías del Ojo , Feto , Enfermedades Renales Quísticas , Adulto , Femenino , Humanos , Masculino , Embarazo , Anomalías Múltiples/genética , Cerebelo/anomalías , Secuenciación del Exoma , Anomalías del Ojo/genética , Feto/anomalías , Heterocigoto , Enfermedades Renales Quísticas/genética , Proteínas de la Membrana/genética , Mutación , Retina/anomalías , Diagnóstico PrenatalRESUMEN
Ankyrin repeat domain containing-protein 11 (ANKRD11), a transcriptional factor predominantly localized in the cell nucleus, plays a crucial role in the expression regulation of key genes by recruiting chromatin remodelers and interacting with specific transcriptional repressors or activators during numerous biological processes. Its pathogenic variants are strongly linked to the pathogenesis and progression of multisystem disorder known as KBG syndrome. With the widespread application of high-throughput DNA sequencing technologies in clinical medicine, numerous pathogenic variants in the ANKRD11 gene have been reported. Patients with KBG syndrome usually exhibit a broad phenotypic spectrum with a variable degree of severity, even if having identical variants. In addition to distinctive dental, craniofacial and neurodevelopmental abnormalities, patients often present with skeletal anomalies, particularly postnatal short stature. The relationship between ANKRD11 variants and short stature is not well-understood, with limited knowledge regarding its occurrence rate or underlying biological mechanism involved. This review aims to provide an updated analysis of the molecular spectrum associated with ANKRD11 variants, investigate the prevalence of the short stature among patients harboring these variants, evaluate the efficacy of recombinant human growth hormone in treating children with short stature and ANKRD11 variants, and explore the biological mechanisms underlying short stature from both scientific and clinical perspectives. Our investigation indicated that frameshift and nonsense were the most frequent types in 583 pathogenic or likely pathogenic variants identified in the ANKRD11 gene. Among the 245 KBGS patients with height data, approximately 50% displayed short stature. Most patients showed a positive response to rhGH therapy, although the number of patients receiving treatment was limited. ANKRD11 deficiency potentially disrupts longitudinal bone growth by affecting the orderly differentiation of growth plate chondrocytes. Our review offers crucial insights into the association between ANKRD11 variants and short stature and provides valuable guidance for precise clinical diagnosis and treatment of patients with KBG syndrome.
Asunto(s)
Fenotipo , Proteínas Represoras , Humanos , Proteínas Represoras/genética , Anomalías Múltiples/genética , Discapacidad Intelectual/genética , Anomalías Dentarias/genética , Anomalías Dentarias/patología , Craneosinostosis/genética , Craneosinostosis/patología , Deleción Cromosómica , Enfermedades del Desarrollo Óseo , FaciesRESUMEN
BACKGROUND: Glass syndrome, derived from chromosomal 2q33.1 microdeletions, manifests with intellectual disability, microcephaly, epilepsy, and distinctive features, including micrognathia, down-slanting palpebral fissures, cleft palate, and crowded teeth. Recently, SATB2 located within the deletion region, was identified as the causative gene responsible for Glass syndrome. Numerous disease-causing variants within the SATB2 coding region have been reported. OBJECTIVE: Given the presentation of intellectual disability and multiple congenital anomalies in a patient with a de novo reciprocal translocation between chromosomes 1 and 2, disruption of the causative gene(s) was suspected. This study sought to identify the causative gene in the patient. METHODS: Long-read whole-genome sequencing was performed, and the expression level of the candidate gene was analyzed. RESULTS: The detection of breakpoints was successful. While the breakpoint on chromosome 1 disrupted RNF220, it was not deemed to be a genetic cause. Conversely, SATB2 is located in the approximately 100-kb telomeric region of the breakpoint on chromosome 2. The patient's clinical features resembled those of previously reported cases of Glass syndrome, despite the lack of confirmed reduced SATB2 expression. CONCLUSION: The patient was diagnosed with Glass syndrome due to the similarity in clinical features. This led us to hypothesize that disruption in the downstream region of SATB2 could result in Glass syndrome. The microhomologies identified in the breakpoint junctions indicate a potential molecular mechanism involving microhomology-mediated break-induced repair mechanism or template switching.
Asunto(s)
Discapacidad Intelectual , Proteínas de Unión a la Región de Fijación a la Matriz , Factores de Transcripción , Humanos , Proteínas de Unión a la Región de Fijación a la Matriz/genética , Proteínas de Unión a la Región de Fijación a la Matriz/metabolismo , Discapacidad Intelectual/genética , Factores de Transcripción/genética , Cromosomas Humanos Par 2/genética , Microcefalia/genética , Rotura Cromosómica , Masculino , Anomalías Múltiples/genética , Epilepsia/genética , Femenino , Cromosomas Humanos Par 1/genéticaRESUMEN
This article reports on the clinical and genetic characteristics of monozygotic twins with Marshall-Smith syndrome (MRSHSS) due to a mutation in the NFIX gene, along with a review of related literature. Both patients presented with global developmental delays, a prominent forehead, shallow eye sockets, and pectus excavatum. Genetic testing revealed a heterozygous splicing site mutation c.697+1G>A in both children, with parents showing wild-type at this locus. According to the guidelines of the American College of Medical Genetics and Genomics, this mutation is considered likely pathogenic and has not been previously reported in the literature. A review of the literature identified 32 MRSHSS patients with splicing/frameshift mutations. Accelerated bone maturation and moderate to severe global developmental delay/intellectual disability are the primary clinical manifestations of patients with MRSHSS. Genetic testing results are crucial for the diagnosis of this condition.
Asunto(s)
Mutación , Factores de Transcripción NFI , Gemelos Monocigóticos , Humanos , Factores de Transcripción NFI/genética , Gemelos Monocigóticos/genética , Anomalías Múltiples/genética , Masculino , Femenino , Anomalías Craneofaciales/genética , Preescolar , Enfermedades del Desarrollo Óseo , Displasia Septo-ÓpticaRESUMEN
ARID1B is the most frequently mutated gene in Coffin-Siris syndrome (CSS). To date, the vast majority of causative variants reported in ARID1B are truncating, leading to nonsense-mediated mRNA decay. In the absence of experimental data, only few ARID1B amino acid substitutions have been classified as pathogenic, mainly based on clinical data and their de novo occurrence, while most others are currently interpreted as variants of unknown significance. The present study substantiates the pathogenesis of ARID1B non-truncating/NMD-escaping variants located in the SMARCA4-interacting EHD2 and DNA-binding ARID domains. Overexpression assays in cell lines revealed that the majority of EHD2 variants lead to protein misfolding and formation of cytoplasmic aggresomes surrounded by vimentin cage-like structures and co-localizing with the microtubule organisation center. ARID domain variants exhibited not only aggresomes, but also nuclear aggregates, demonstrating robust pathological effects. Protein levels were not compromised, as shown by quantitative western blot analysis. In silico structural analysis predicted the exposure of amylogenic segments in both domains due to the nearby variants, likely causing this aggregation. Genome-wide transcriptome and methylation analysis in affected individuals revealed expression and methylome patterns consistent with those of the pathogenic haploinsufficiency ARID1B alterations in CSS cases. These results further support pathogenicity and indicate two approaches for disambiguation of such variants in everyday practice. The few affected individuals harbouring EHD2 non-truncating variants described to date exhibit mild CSS clinical traits. In summary, this study paves the way for the re-evaluation of previously unclear ARID1B non-truncating variants and opens a new era in CSS genetic diagnosis.