XPR1 encodes the only known phosphate exporter in human cells and regulates the export of inorganic phosphate (Pi). To date, heterozygous pathogenic variants have been reported to be associated with autosomal-dominant idiopathic basal ganglia calcification-6 (IBGC6; MIM: 616413). We collate clinical information on individuals with biallelic XPR1 variants and use in silico and cell-based studies to evaluate pathogenicity. Four consanguineous families have been documented, with a severe neonatal phenotype presenting with persistent pulmonary hypertension, chronic lung disease, cardiomyopathy, and hypophosphatemia. Affected individuals exhibit microcephaly, intracranial calcifications, and profound neurodevelopmental impairment; the prognosis is generally poor. Exome and Sanger sequencing confirmed segregation with homozygosity for a rare, likely deleterious, biallelic XPR1 variant NM_004736.4: c.1811G>A: p.Arg604Gln. Analysis of primary cell lines showed stable expression of the XPR1 protein. In silico structural analysis supported the variant's deleterious nature. Published mutagenesis studies demonstrate that mutations at the arginine residue (Arg604) within the second putative Pi coordination site substantially impair Pi export in functional flux assays. This study establishes a link between a novel severe neonatal disease and specific biallelic variants in XPR1 that result in a loss-of-function phenotype.

Mandibulofacial dysostosis, Guion-Almeida type is an autosomal dominant disorder characterized by craniofacial malformations and intellectual disability. Pathogenic EFTUD2 variants represent the primary genetic etiology of Mandibulofacial dysostosis, Guion-Almeida type. In this report, we describe a family with Mandibulofacial dysostosis, Guion-Almeida type, where two consecutive singleton pregnancies were affected due to the presence of a novel EFTUD2 variant in their mosaic mother. A 30-year-old Han Chinese pregnant woman (gravida 3, para 0) chose amniocentesis for genetic diagnosis at 19 weeks and 4 days of gestation due to the presence of a pathogenic EFTUD2 variant [NM_004247.4:c.2444_2445del (p.V815Gfs*69)] in her second fetus. Copy number variation sequencing detected no chromosomal aneuploidies or copy number variations. However, the c.2444_2445del variant was once again identified in her third fetus via whole exome sequencing. Sanger sequencing results unexpectedly detected that the woman displayed low-level mosaicism of this variant. Finally, the woman decided to terminate the pregnancy at 23 weeks and 3 days of gestation. The literature review indicated isolated or nonisolated prenatal ultrasound abnormalities, such as micrognathia, polyhydramnios, a small or absent stomach bubble, and microcephaly, may serve as valuable indications for prenatal diagnosis of Mandibulofacial dysostosis, Guion-Almeida type. This family case expands the mutational spectrum of Mandibulofacial dysostosis, Guion-Almeida type and highlights familial occurrence of mosaicism in parents without Mandibulofacial dysostosis, Guion-Almeida type symptoms. Therefore, comprehensive genetic counseling and consideration of prenatal testing for subsequent pregnancies are advised.

Axenfeld-Rieger syndrome/anomaly (ARS) is a rare genetic disorder with an autosomal dominant inheritance pattern, characterized by dysgenesis of the anterior segment of the eye. It may present with systemic anomalies (Axenfeld-Rieger syndrome) or without (Axenfeld anomaly) and may sometimes be associated with multiple congenital malformations. The estimated prevalence ranges from 1 in 50,000 to 1 in 200,000 live births, with an approximate rate of 1 in 100,000, but no epidemiological studies have been conducted to date. A clinical diagnosis of Axenfeld-Rieger syndrome requires the presence of both Axenfeld and Rieger ocular anomalies, accompanied by extraocular systemic features. Ocular manifestations include iris abnormalities, posterior embryotoxon, juvenile-onset glaucoma (a common complication), and dysgenesis of the iridocorneal angle with iridocorneal adhesions. The most commonly observed systemic anomalies include: umbilical defects; craniofacial dysmorphism; dentofacial abnormalities, such as Class III malocclusion due to maxillary hypoplasia, oligodontia, dental malformations (taurodontism, root dysplasia), microdontia, hypodontia, and anodontia; hearing impairment (partial or complete sensorineural hearing loss); and cardiac anomalies, including non-congenital heart disease and mitral valve insufficiency. Additional anomalies may include hypospadias in males, anal stenosis, endocrine disorders (notably growth retardation) secondary to pituitary dysfunction, psychomotor delay, and various neurological malformations such as Dandy-Walker malformation, mega cisterna magna, posterior fossa cysts, cerebellar vermis hypoplasia, ventriculomegaly, aprosencephaly, cerebral atrophy, microcephaly, arteriovenous malformations (AVM), and digital anomalies such as camptodactyly. Diagnosis is typically made in infancy, based on iris anomalies such as corectopia (displacement of the pupil), polycoria (multiple pupils), and iris hypoplasia. Posterior embryotoxon is frequently observed upon slit-lamp examination. Given the clinical variability, a comprehensive pediatric assessment is essential to identify systemic anomalies and distinguish Axenfeld-Rieger syndrome from the isolated Axenfeld anomaly.

The CHAMP1 (Chromosome Alignment-Maintaining Phosphoprotein 1) gene encodes a nuclear protein crucial for maintaining proper chromosome alignment and genomic stability during cell mitosis. Heterozygous variants of this gene, particularly de novo truncating mutations, are the primary cause of a rare neurodevelopmental disorder: autosomal dominant intellectual disability Autosomal Dominant Mental Retardation 40 (MRD40) or CHAMP1-related Neurodevelopmental Disorder (CHAND). The core clinical features of this disorder include moderate to severe global developmental delay, intellectual disability, significant language impairment, and distinctive facial features. Additionally, patients may exhibit abnormal muscle tone, behavioral issues (such as autism spectrum disorder traits and attention deficit hyperactivity disorder), epilepsy, microcephaly, and involvement of other multi-systemic complications, including gastrointestinal dysfunction. The pathogenic mechanisms of CHAMP1 truncating mutations remain debated, with main hypotheses including haploinsufficiency and dominant-negative effect or gain-of-function, where the latter better explains the more severe clinical phenotypes observed in some patients. Although neurological manifestations are the research focus of CHAMP1-related disorders, the involvement of other systems such as the digestive system-particularly symptoms like repeated vomiting-has been underreported and lacks systematic research within this disease spectrum. This review aims to integrate the latest research progress on the molecular functions of the CHAMP1 gene, the pathogenic mechanisms of its variants, and the clinical phenotype spectrum of related neurodevelopmental disorders. Based on clinical observations, we also preliminarily explored the potential association between CHAMP1 gene variation and gastrointestinal symptoms (especially recurrent vomiting), with the goal of providing valuable references for clinical diagnosis, management, and future research directions for this rare disease.

Microcephaly with or without chorioretinopathy, lymphedema, or mental retardation (MCLMR) is a rare autosomal dominant disease caused by variants in the KIF11 gene. Additionally, recent advances in genetic testing have led to the increasing identification of KIF11 gene variants in FEVR patients. Harboring similar point variants in the KIF11 gene, patients exhibit striking variability in clinical manifestations. However, comprehensive clinical characterization of MCLMR patients with KIF11 variants are only mentioned by a few case reports and the genotypic and phenotypic variability in KIF11-associated disease was not thoroughly investigated. Therefore, one case is discussed alongside a systematic review of published MCLMR cases to clarify genotype-phenotype correlations. An 8-year-old boy was referred to our clinic due to poor vision. Clinical evaluation revealed microcephaly, characteristic chorioretinopathy and mild developmental delay, in the absence of primary lymphedema. Additional findings included special facial features, bilateral simian crease and metabolic abnormalities featuring elevated urine glucose and ketone bodies despite normoglycemia. Brain magnetic resonance imaging (MRI) demonstrated microcephaly with simplified gyration, delayed myelination, and cortical thickening. Whole exome sequencing (WES) identified a previously reported synonymous variant in KIF11 (c.2922G > A, p.Pro974=), which was confirmed and co-segregated by Sanger sequencing. A Chinese boy was diagnosed with MCLMR following the identification of a pathogenic KIF11 gene point variant, as classified according to ACMG guidelines. Combined with previously reported literature, a total of 55 pathogenic KIF11 variants have been identified, distributed throughout the entire gene. A recurrent mutational hotspot (c.1159 C > T, p.Arg238*) was observed. Additionally, frameshift and splicing variants collectively account for over 50% of cases. Notably, missense variants are associated with more severe phenotypic manifestations, suggesting a genotype-phenotype correlation. This case, supported by comprehensive clinical data, contributes to a more complete elucidation of the phenotypic spectrum of KIF11-related disorders. The online version contains supplementary material available at 10.1186/s12886-025-04261-y.