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Neurodevelopmental disorders (NDDs) have heterogeneity in both clinical characteristics and genetic factors. EBF3 is a recently discovered gene associated with a syndromic form of NDDs characterized by hypotonia, ataxia and facial features. In this study, we report twelve unrelated individuals with EBF3 variants using next-generation sequencing. Five missense variants (four novel variants and one known variant) and seven copy number variations (CNVs) of EBF3 gene were identified. All of these patients exhibited developmental delay/intellectual disability. Ataxia was observed in 33% (6/9) of the patients, and abnormal muscle tone was observed in 55% (6/11) of the patients. Aberrant MRI reports were noted in 64% (7/11) of the patients. Four novel missense variants were all located in the DNA-binding domain. The pathogenicity of these variants was validated by in vitro experiments. We found that the subcellular protein localization of the R152C and F211L mutants was changed, and the distribution pattern of the R163G mutant was changed from even to granular. Luciferase assay results showed that the four EBF3 mutants' transcriptional activities were all significantly decreased (p

Craniosynostosis is a premature fusion of cranial sutures, resulting in abnormally shaped skull and brain development disorder. The description of craniosynostosis in patients with BCL11B mutations is rare. Here, we firstly report a 25-month-old Chinese boy with a novel frameshift variant in BCL11B gene. The patient was identified c.2346_2361del by whole-exome sequencing and was confirmed to be de novo by parental Sanger sequencing. This patient presented clinical phenotype of craniosynostosis as well as global developmental delay. He had a small mouth, thin upper lip, arched eyebrows, a long philtrum, midfacial hypoplasia and craniosynostosis. Brain MRI showed brain extracerebral interval and myelination changes, and brain CT with 3D reconstruction showed multi-craniosynostosis. Our study expands the clinical phenotypes of patients with BCL11B gene mutation, and our findings may help guide clinical treatment and family genetic counseling.

BackgroundGalloway–Mowat syndrome type 3 (GAMOS3) is an extremely rare and severe autosomal-recessive disease characterized by early-onset nephrotic syndrome (NS), microcephaly and neurological impairment. Reported GAMOS cases have gradually increased since pathogenic OSGEP variants were identified as the aetiology in 2017.MethodsUsing whole-exome sequencing and a data analysis process established by Children's Hospital of Fudan University, the clinical and molecular features of 3 infants with OSGEP mutations were summarized. Literature regarding the clinical features of GAMOS3 caused by OSGEP variants was reviewed.ResultsThirty-seven individuals (3 from this study) from 34 families were included. Twenty-two different OSGEP variants were identified. The c.740G>A (p.Arg247Gln) variant in OSGEP was detected in 15 families (44%), all from Asia. Most affected individuals (including patients I and II in this study) showed a typical phenotype, including microcephaly (92%) with brain anomalies (97%), developmental delay (81%), congenital NS (54%), and craniofacial (94%) and skeletal dysmorphism (84%). Renal manifestations varied from proteinuria (94%, median onset = 1.5 months) to NS (83%) and end-stage renal disease (48%, 11 months) during follow-up. Patients with congenital NS had a lower survival probability (median survival time = 3 months) than those without congenital NS (78 months) (P < 0.01, log-rank test).ConclusionGAMOS3 is a progressive renal-neurological syndrome with a poor prognosis, especially with congenital NS. Microcephaly with dysmorphic features are vital clues to further evaluate renal impairment and brain anomalies. Timely molecular diagnosis is crucial for clinical decision-making, appropriate treatment and genetic counselling.

MEGDEL syndrome and SATB2-associated syndrome (SAS) are both rare congenital disorders with poor prognoses caused by gene mutations. We present the case of a 2-day-old girl with an unexplained abnormal liver function, feeding problem, and dystonia. Using next-generation sequencing, we identified two novel mutations in SERAC1 and a mutation in SATB2. Now, she is 15 months old and has the characteristics of SAS, such as downslanting palpebral fissures and delayed primary dentition. Besides the typical phenotypes of MEGDEL syndrome, such as hypertonia, failure to thrive, deafness, and motor regression, she has progressive cholestasis and is prone to high serum lactate after rehabilitation training and hypoglycemia with low ketone under starving conditions. These phenotypes substantially differ from the transient liver function abnormalities and hypoglycemia reported in the literature.

Neonatal metabolic acidosis (NMA) is a common problem, particularly in critically ill patients in neonatal intensive care units (NICUs). Complex etiologies and atypical clinical signs make diagnosis difficult; thus, it is crucial to investigate the underlying causes of NMA rapidly and provide disorder-specific therapies. Our study aims to provide an overview of the genetic causes of NMA in patients from NICUs. We performed next-generation sequencing (NGS) on neonates with NMA from January 2016 to December 2019. Clinical features, genetic diagnoses, and their effects on clinical interventions were collected for analysis. In the 354 enrolled patients, 131 (37%) received genetic diagnoses; 95 (72.5%) of them were autosomal recessively inherited diseases. Two hundred and fifteen variants spanning 57 genes were classified as pathogenic (P) or likely pathogenic (LP) in 131 patients. The leading cause was metabolic disorders due to 35 genes found in 89 patients (68%). The other 42 NMA patients (32%) with 22 genes had malformations and renal, neuromuscular, and immune-hematological disorders. Seven genes (MMUT, MMACHC, CHD7, NPHS1, OTC, IVD, and PHOX2B) were noted in more than four patients, accounting for 48.9% (64/131) of the identified P/LP variants. Forty-six diagnosed patients with uncorrected NMA died or gave up. In conclusion, 37% of neonates with metabolic acidosis had genetic disorders. Next-generation sequencing should be considered when investigating the etiology of NMA in NICUs. Based on early molecular diagnoses, valuable treatment options can be provided for some genetic diseases to achieve better outcomes.