To explore the clinical features and genetic etiology of a child with Hoyeraal-Hreidarsson syndrome (HHS). A child with HHS diagnosed at the Affiliated Hospital of Jining Medical University due to "developmental delay and anaemia" on April 27, 2024 was selected as the study subject. Clinical data of the child was collected. Genomic DNA was extracted from peripheral blood samples of the child and his family members. Whole-exome sequencing was carried out, and candidate variant was verified by Sanger sequencing of his family members and bioinformatics analysis using CASAVA v1.8.2. The pathogenicity of the candidate variant was rated according to the Standards and Guidelines for the Interpretation of Sequence Variants released by the American College of Medical Genetics and Genomics (ACMG). Relevant literature on HHS cases reported in China was reviewed to analyze the clinical and genetic characteristics. This study was approved by the Medical Ethics Committee of the Hospital (Ethics No.: 2024-10-C003). The child, a 7-month-old boy, had mainly manifested with growth retardation, developmental delay, microcephaly, cerebellar hypoplasia, immunodeficiency and bone marrow failure. Routine blood test indicated pancytopenia. The immunological workup showed reduction of B cells, NK cells and immunoglobulins. Cranial MRI demonstrated the volume of bilateral cerebellar hemispheres and brainstem and corpus callosum was small. Whole-exome sequencing revealed that he has harbored a hemizygous c.103_105del (p.Glu35del) variant of the DKC1 gene. Sanger sequencing showed that his mother and two sisters have carried the same variant. Based on the ACMG guidelines, the variant was predicted to be likely pathogenic (PM1+PM4+PS4_Supporting+PM2_Supporting). Four relevant literature were retrieved, which has involved 8 HHS cases. Together with the patient from this study, they have consisted of 8 males and 1 females. The most common symptoms of the 9 patients were blood system abnormalities and developmental delay. All patients had shown cerebellar dysplasia and anemia/erythrocytopenia. Among them, 3 cases have harbored TINF2 gene variants, and 6 cases had harbored DKC1 gene variants. The c.103_105del variant has not been reported in China previously. The hemizygous c.103_105del (p.Glu35del) variant of the DKC1 gene probably underlay the disease in this child. Above finding has expanded the mutational and phenotypic spectra of the DKC1 gene, and has facilitated early diagnosis of HHS in this child.

USP9X gene variations have been associated with the rare syndrome female-restricted X-linked syndromic intellectual disability (MRXS99F). Loss-of-function mutations in USP9X gene is primarily characterized by development delay, speech and motor disorders, special facial features and multiple congenital malformations. We reported a newborn who presented with special facial features and developmental delay. We performed whole-genome sequencing and identified a rare novel heterozygous USP9X variant, c.4071-4077delCTTTACT (p.Thr1359Trpfs*19). To date, only seven USP9X variants in infants have been reported. Affected individuals typically exhibit a spectrum of congenital anomalies, including craniofacial dysmorphisms (such as hypertelorism, flat nasal bridge, and cleft palate), skeletal abnormalities (such as limb shortening, scoliosis, and rib anomalies), and neurological deficits (including severe intellectual disability, epilepsy, and motor delay). The radio logical tests revealed structural anomalies, such as corpus callosum agenesis and congenital hip dysplasia. This study expands the genotypic and clinical phenotypic spectrum of USP9X-related MRXS99F and reinforces the utility of whole-genome sequencing in early diagnosis and genetic counseling.

Female-restricted X-linked syndromic intellectual developmental disorder-99 is an ultrarare neurodevelopmental disorder linked to X, manifesting in female individuals due to mutations in the USP9X gene. It is characterized by developmental delays, behavioral alterations, and moderate-to-severe intellectual disability. The USP9X gene plays critical roles in protein turnover and the regulation of essential pathways during neural development. This work describes the case of a Brazilian patient with female-restricted X-linked syndromic intellectual developmental disorder-99 with a variant not found in databases such as Decipher and ClinVar. Information was obtained from the Center for Rehabilitation and Readaptation Dr. Henrique Santillo electronic medical record system, and exams were conducted by partner laboratories of the Unified Health System. Documenting cases in different populations enriches the knowledge of genetic variations, guides personalized treatments, and expands the field of medical genetics, underscoring the importance of this study. A 3-year-old female patient of Pardo admixed ethnicity from northern Brazil was referred to the Center for Rehabilitation and Readaptation Dr. Henrique Santillo for suspected genetic disorders. The child was born after an uneventful pregnancy but faced neonatal complications, including cardiopulmonary arrest and jaundice, requiring intensive care unit admission. She was diagnosed with nonprogressive encephalopathy and neuropsychomotor developmental delay. Additional tests revealed structural anomalies, such as corpus callosum agenesis and congenital hip dysplasia. Various genetic tests were performed, but only whole exome sequencing revealed a pathogenic variant in the USP9X gene, associated with female-restricted X-linked syndromic intellectual developmental disorder-99. We report the case of a child with a heterozygous pathogenic variant in the USP9X gene, located at Xp11.4 and presenting a wide range of phenotypes. The cytosine-to-thymine substitution resulted in a premature stop codon, causing female-restricted X-linked syndromic intellectual developmental disorder-99. The mutation leads to protein function loss due to haploinsufficiency, resulting in a dominant X-linked disorder. Loss-of-function mutations in the USP9X gene cause intellectual disability and congenital anomalies, with several craniofacial anomalies observed in the patient. Despite the de novo nature of most loss-of-function variants, maternal testing is crucial for estimating recurrence risk. Genetic investigation confirmed the variant's pathogenicity, highlighting diagnostic challenges and the importance of genetic research in understanding and managing female-restricted X-linked syndromic intellectual developmental disorder-99.

Objectives/Background: Aarskog-Scott syndrome (AAS), also known as faciogenital dysplasia, is a rare X-linked genetic disorder primarily characterized by its diverse physical manifestations. Previous evidence suggests a potential association between AAS and neurodevelopmental disorders, including autism spectrum disorder (ASD). Methods: This case study presents a male adolescent with ASD and a novel genetic variant in FGD1 underlying AAS. We conducted comprehensive clinical, genetic, and behavioral assessments to characterize the neurodevelopmental presentation. Moreover, we examined the existing literature on AAS and comorbid neurodevelopmental disorders. Results: The patient demonstrated features consistent with both AAS and ASD, presenting with characteristic physical features of AAS and meeting diagnostic criteria for ASD on both ADI-R and ADOS-2. Cognitive assessment revealed above-average nonverbal IQ (Leiter-3, NVIQ = 115), while adaptive functioning was notably impaired (Vineland composite score = 65). Executive function deficits were identified through several assessments, though ADHD diagnostic criteria were not met. The literature review considered 64 studies, including 151 individuals with AAS. ASD was observed in 4.0%, Attention Deficit/Hyperactivity Disorder (ADHD) in 10.6%, and Intellectual Disability (ID) in 14.2% of cases. Conclusions: The combination of ASD with preserved nonverbal intelligence but impaired adaptive functioning in this AAS case demonstrates the complex neurodevelopmental manifestations possible in this rare genetic condition. The prevalence of neurodevelopmental disorders among people with AAS may be higher than their prevalence in the general population. However, a comprehensive assessment of developmental progress was rarely performed in previous studies, which may lead to systematic underestimation of co-occurring neurodevelopmental difficulties in AAS.

To explore the clinical phenotype and genetic etiology of a neonate with X-linked alpha-thalassemia mental retardation syndrome (ATR-X) caused by ATRX gene variant, and review related literature on children with ATR-X caused by ATRX gene variants. A case of ATR-X neonate who was transferred to the First Affiliated Hospital of Zhengzhou University on February 11, 2022 for poor effect of treatment in the neonatology department of the hospital where he was born for 4 days due to "postnatal slow response, groaning, and cyanosis of the skin for 30 min" was selected as the study subject. 3 mL of peripheral blood was collected from the child and their parents, and genomic DNA was extracted for whole exome sequencing (WES). Sanger sequencing was used to verify the pathogenic gene variations in the child's family. The pathogenicity of genetic variant sites was assessed based on the Standards and Guidelines for the Interpretation of Sequence Variants by American College of Medical Genetics and Genomics (ACMG). The amino acid sequence conservation analysis of relevant variant proteins was conducted by the Universal Protein Resource Database (UniProt) and visual analysis of these variant proteins was performed by Swiss online protein three-dimensional modeling database (SWISS-MODEL). Using keywords such as "ATRX gene" and " X-linked alpha-thalassemia mental retardation syndrome" both in Chinese and English, relevant literature on ATR-X children caused by ATRX gene variants was retrieved from the CNKI, Wanfang Data Knowledge Service Platform, and PubMed databases, and the clinical phenotypes of ATR-X patients reported in the retrieved literature were analyzed. The literature retrieval time was set from the establishment of each database to December 31st, 2023. This study followed the research procedures approved by the Ethics Committee of the First Affiliated Hospital of Zhengzhou University (Ethics No. 2023-KY-1360-002), and informed consent of clinical study was signed by the guardian of the child. The child in this study presented with symptoms such as delayed response, feeding difficulties accompanied by vomiting, low body temperature, hypotonia in all extremities, apnea, abnormal hearing screening, and a Neonatal Behavioral Neurological Assessment (NBNA) score of 19 (lower than the normal range).Hemoglobin (Hb) electrophoresis suggested the presence of α-thalassemia. The results of WES and Sanger sequencing revealed a hemizygous missense variant c.668G>A (p.C223Y) in exon 9 of the ATRX gene in the child of the study, neither of the parents of the child carried this variant, indicating that it is a de novo variant. Based on the Standards and Guidelines for the Interpretation of Sequence Variants released by ACMG, this gene variant was assessed as pathogenic (PS2+PM2_Supporting+PP3_Strong+PP4_Strong). The results of amino acid sequence analysis revealed that the pathogenic variant site normally encodes cysteine, which is highly conserved among various animal species. This pathogenic variant can lead to alterations in the hydrogen bonding structure of ATRX protein, thereby affecting its structural stability. Based on the clinical manifestations and genetic testing results of the child in this study, a diagnosis of ATR-X syndrome was established Based on the literature retrieval strategy established in this study, 13 relevant articles concerning ATR-X syndrome in children caused by ATRX gene variants were retrieved, including 5 Chinese articles and 8 English articles, involving a total of 311 ATR-X children. Including the child in this study, the total number of ATR-X children reaches 312. All 312 children were male and presented with mental retardation. Among them, 45.8% (143/312) had coexisting α-thalassemia, 45.2% (141/312) had abnormal genital appearance, 44.2% (138/312) had facial malformations, and 30.8% (96/312) had hypotonia. Other phenotypes included microcephaly, skeletal dysplasia, among others. The ATR-X child in this study exhibit a range of clinical phenotypes, including delayed growth and development, facial malformation, abnormal genital appearance, apnea, vomiting symptoms, among others. The de novo variant of ATRX gene c.668G>A (p.C223Y) was identified as the genetic etiology. This study contributes to the expansion of the clinical phenotype spectrum and genetic variation spectrum of ATR-X children.