Aug 2026· Frontiers in Genetics· 0 citations· 15 references
TL;DR
The proband, despite carrying a truncating variant, presented without classic digital anomalies or ocular involvement, underscoring that even loss-of-function alleles can produce atypical CSS4 phenotypes.
Abstract
Coffin-Siris syndrome type 4 (CSS4; OMIM 614609) is a rare autosomal dominant disorder caused by variants in SMARCA4, encoding the BRG1 ATPase subunit of the BAF chromatin-remodeling complex. Although classically characterized by intellectual disability, distinctive facial features, and fifth digit hypoplasia, the phenotypic spectrum is broad and includes autism spectrum disorder (ASD) without typical somatic features. We report a 3-year-old Chinese girl with global developmental delay, ASD features, characteristic facial features, and a documented normal ophthalmologic examination in whom whole-exome sequencing identified a novel heterozygous
de novo
frameshift duplication, c.4767dup (p.Ser1590Ilefs*39), in SMARCA4 (NM_003072), classified as Pathogenic (PVS1+PM2_Supporting + PM6). Notably, she lacked fifth digit hypoplasia and had no structural ocular anomalies on detailed ophthalmologic evaluation. A systematic review of the literature identified 39 genetically confirmed SMARCA4-related CSS4 cases; combined with our patient, 40 cases were analyzed. Intellectual disability was universal (100%), ASD manifestations occurred in 42.5%, and fifth digit hypoplasia was present in only 55.0%. Truncating variants (37.5% of the cohort) showed descriptive trends toward higher prevalence of fifth digit hypoplasia and ocular abnormalities than missense variants, though these differences did not reach statistical significance. Our proband, despite carrying a truncating variant, presented without classic digital anomalies or ocular involvement, underscoring that even loss-of-function alleles can produce atypical CSS4 phenotypes. For children with developmental delay, ASD, and distinctive facial features—regardless of the presence of classic digital anomalies—genetic testing for SWI/SNF complex genes should be considered. Given current limited evidence, carriers of truncating variants should be counseled regarding potential tumor predisposition, and individualized surveillance strategies may be considered pending further data.
Background Autism spectrum disorder (ASD) is a highly heterogeneous neurodevelopmental disorder. A previous study by Nizon et al. indicated that some children with intellectual disability (ID) carrying de novo MED12L mutations exhibited mild to moderate autistic features. However, the relationship between MED12L and ASD remains unclear. Case presentation Here we reported a male child with severe autistic features carrying a novel de novo heterozygous truncating mutation of MED12L (NM_053002.5:c.586C>T, p.(Arg196Ter)). He was diagnosed with ASD according to ICD-11 and DSM-5 criteria. Clinical examination indicated that this child exhibited severe autistic features and several dysmorphic features, including a flat nasal bridge, bulbous nasal tip, thin upper lip, and triangular face. Magnetic resonance imaging (MRI) of the brain revealed an enlarged perivascular space in the right temporal lobe. Conclusion This case demonstrates that this de novo heterozygous truncating mutation in MED12L may be involved in the development of ASD, and haploinsufficiency of MED12L may be associated with severe autistic features. Obvious clinical manifestations and dysmorphic features in this child with a truncating mutation in MED12L expand the phenotypic spectrum of MED12L-related cases and warrant further functional studies to elucidate the relationship between MED12L and ASD.
Zhiliu Wu, Chuanyong Xu, Jierong Chen et al.· Frontiers in Psychiatry· 0 citations
Background: Kabuki syndrome is a rare multisystem neurodevelopmental disorder usually caused by pathogenic KMT2D or KDM6A variants, although a substantial minority of clinically typical patients remain molecularly unresolved. Autism spectrum disorder (ASD) has been reported in this population, but its prevalence and relationship to genotype remain poorly characterized. Case Presentation: We report a 12-year-old Moroccan boy, born to consanguineous parents, referred for severe behavioral disturbances including psychomotor hyperactivity, self-injurious behavior, and marked language delay. Physical examination showed characteristic craniofacial dysmorphism, long palpebral fissures with eversion of the lateral lower eyelids, blue sclerae, broad arched eyebrows, a depressed nasal tip, and a high-arched palate, together with microcephaly, postnatal growth restriction, infantile hypotonia, a waddling gait, and possible scoliosis, fulfilling international consensus criteria on dysmorphology, growth restriction, hypotonia, and musculoskeletal abnormalities for a clinical diagnosis of Kabuki syndrome. He also presented with severe ASD, attention-deficit/hyperactivity disorder, intellectual developmental disorder, and generalized epilepsy, established according to DSM5 criteria. Whole-exome sequencing identified no pathogenic variant in KMT2D or KDM6A, but revealed a heterozygous variant of uncertain significance in YWHAG (NM_012479.3:c.340G>A; p.Glu114Lys), a gene associated with developmental and epileptic encephalopathy. Pharmacological management included extended-release methylphenidate, which was discontinued because of paradoxical worsening of hyperactivity, followed by low-dose aripiprazole, which improved self-injurious behavior and agitation but caused a persistent tremor. Conclusions: This case shows that a well-characterized clinical gestalt remains sufficient to diagnose Kabuki syndrome despite negative first-line genetic testing, and that residual possibilities
M. Nokrou, S. Bounouh, Z. Maataoui et al.· Scholars Journal of Medical...· 0 citations
Cytochrome P450 oxidoreductase deficiency (PORD) is an ultra-rare autosomal recessive disorder within the congenital adrenal hyperplasia (CAH) spectrum, characterized by a broad clinical spectrum involving steroidogenesis defects, genital anomalies, and skeletal abnormalities.
We report a phenotypically female neonate with a 46,XY karyotype whose postnatal diagnostic evaluation was initiated after newborn screening revealed elevated 17-hydroxyprogesterone (17-OHP) concentration. The patient presented with mild hypertelorism, mild nasal hypoplasia, and low-set bilateral ears, along with female external genitalia consistent with disorder of sex development (DSD) and anal atresia. Radiological evaluation revealed femoral bowing and subsequent fracture. The craniofacial and skeletal abnormalities were consistent with the features of Antley-Bixler syndrome (ABS). Endocrine evaluation revealed elevated progesterone, markedly reduced testosterone, and secondary hyperaldosteronism. Genetic analysis identified three novel variants in the
POR
gene (NM_001395413.1): the patient harbored a paternal c.1187_1195dup (p.Pro396_Glu398dup) variant and two maternally inherited variants in
cis
, c.1447G>A (p.Gly483Ser) and c.1806 + 4_1806 + 28del. Protein structural modeling predicted that the p.Pro396_Glu398dup and p.Gly483Ser may disrupt the flavin adenine dinucleotide (FAD)–binding domain. RNA sequencing (RNA-seq) confirmed that the intronic variant c.1806 + 4_1806 + 28del caused aberrant splicing, resulting in partial intron retention and predicted impairment of the nicotinamide adenine dinucleotide phosphate (NADPH)–binding domain. According to American College of Medical Genetics and Genomics (ACMG) guidelines and incorporating functional evidence, c.1187_1195dup and c.1806 + 4_1806 + 28del were reclassified as likely pathogenic (LP), whereas c.1447G>A remained a variant of uncertain significance (VUS).
This study describes a neonate with PORD caused by three novel POR variants and expands the known clinical spectrum of PORD by identifying rare manifestations including anal atresia and hearing loss. RNA-seq provided valuable functional evidence for variant interpretation and facilitated accurate molecular diagnosis. These findings highlight the importance of integrating genetic phasing, transcript-level functional analysis, and comprehensive clinical evaluation for precise diagnosis and counseling in rare endocrine disorders.
Wen-Ting Zhang, Jun-Feng Zeng, Yan-Jing Li et al.· Frontiers in Endocrinology· 0 citations
Background: Variants in SOX4 cause intellectual developmental disorder with speech delay and dysmorphic facies (IDDSDF), an autosomal dominant disorder characterized by global developmental delay, mild-to-severe intellectual disability, speech delay, distinctive facial features, digital anomalies, congenital heart defects (unique), and behavioral abnormalities. To date, only a limited number of patients have been described and the phenotypic spectrum of this disorder has yet to be fully delineated. Methods: Clinical data from three patients were collected, including clinical features, growth and developmental profiles, neuropsychological assessments, and urogenital evaluations. Whole-exome sequencing (WES) was performed to screen for candidate variants, and variant pathogenicity was interpreted following the American College of Medical Genetics and Genomics (ACMG) guidelines. Results: All three patients carried previously unreported de novo truncating variants in SOX4: c.583C>T (p.Gln195*), c.1347del (p.Cys450Alafs*5), and c.153G>A (p.Trp51*). Regarding the clinical phenotypes, Patient 3 (P3) was similar to previously reported cases, whereas Patient 1 (P1) and Patient 2 (P2) each exhibited distinctive features on the basis of overlapping with previous reports: P1 presented with severe hypospadias accompanied by cryptorchidism; to our knowledge, no case with this predominant clinical feature has been reported previously. P2 exhibited nystagmus, a novel phenotype not yet reported in the literature. Conclusions: We report three previously unreported de novo truncating variants in SOX4, expand the phenotypic spectrum of SOX4-related disorders to include nystagmus for the first time, and document one patient presenting with severe hypospadias and cryptorchidism. Our findings further expand the mutational and clinical phenotypic spectra of SOX4, underscore the marked clinical heterogeneity of this disorder, and provide new evidence to facilitate clinical recognition and genetic counseling.
H. Miao, Ting Zhang, Kexin Fang et al.· Genes· 0 citations
The novel NR2F1 variant was classified as likely pathogenic according to ACMG guidelines, confirming the diagnosis of BBSOAS and the ARF3 variant, identified as a secondary finding of uncertain clinical significance, is unlikely to account for the patient's phenotype.
Sina Babaei, Haneieh Honarmand, Mortaza Bonyadi et al.· Molecular Biology Reports· 0 citations
This study contributes additional cases to the expanding phenotypic and mutational spectrum of ZNF292-related neurodevelopmental disorder and indicates growth retardation was observed in all eight individuals, but given the limitations of a single-center referral cohort, this observation should be interpreted with caution and requires validation in larger studies.
Yaping Shen, Rongrong Pan, Chen Liu et al.· Genes· 0 citations
