Claes-Jensen syndrome is a rare X-linked syndromic neurodevelopmental disorder by pathogenic variants in lysine specific demethylase 5C (KDM5C), a lysine-specific histone demethylase. In this study, clinical evaluations were conducted in affected individuals and carrier females. X-chromosome inactivation (XCI) assays were performed to assess genotype-phenotype correlations. Functional studies evaluated variant effects on RNA transcription, protein expression, and stability. Zebrafish models were used for in vivo validation. RNA sequencing with KEGG and GO analyses identified dysregulated genes and pathways, further confirmed in zebrafish. Two novel KDM5C variants NM_004187.5:c.3019del and NM_004187.5:c.782-2A>T were identified in unrelated families with X-linked ID. Affected males presented with short stature, microcephaly, language delay, and intellectual disability, while carrier females showed milder features including learning difficulties and short stature. Skewed XCI in some carriers suggested a role in phenotypic variability. Both variants impair RNA transcription, protein expression and stability. Zebrafish models recapitulated neurodevelopmental and behavioral abnormalities. Transcriptomic analyses revealed disrupted antiviral and interferon-related signaling, implicating aberrant immune activation. Pharmacologic inhibition of the Toll-like receptor pathway ameliorated mutant phenotypes, highlighting neuroinflammation as a potential therapeutic target for KDM5C-related disorders. These findings expand the mutational spectrum of KDM5C-associated ID and uncover a novel pathogenic mechanism between KDM5C dysfunction, protein instability, and dysregulated inflammatory signaling.

Cohesinopathies are rare multisystem disorders caused by defects in the cohesin complex, which is critical for chromosome segregation, DNA repair, replication, heterochromatin formation and gene transcription regulation. Stromal antigen 2 (STAG2), a key cohesin component, is linked to neurodevelopmental disorders such as X-linked holoprosencephaly 13 and Mullegama-Klein-Martinez syndrome (MKMS). Polycystic kidney disease (PKD), particularly autosomal dominant PKD (ADPKD), is characterized by renal cysts and is commonly associated with variants in the PKD1 gene. In the present study, a Chinese family was enrolled, which included an infant diagnosed with MKMS and familial PKD. Trio whole-exome sequencing (trio-WES) was performed to identify a heterozygous in-frame deletion variant in STAG2 [NM_001042750.2:c.1775_1777del, p.(Pro592del)] and a heterozygous frameshift variant in PKD1 [NM_001009944.3:c.8985delC, p.(Ser2996fs*78)] in the proband. The STAG2 variant [c.1775_1777del, p.(Pro592del)] was confirmed by Sanger sequencing to be absent in other family members and was therefore de novo. By contrast, the PKD1 variant [c.8985delC, p.(Ser2996fs*78)] was identified in the mother, aunt and grandmother of the proband. The proband exhibited clinical features consistent with STAG2-related disorders, including seizures, global developmental delay, short stature, microcephaly, hypotonia, dysmorphic features, incomplete cleft palate, micrognathia, spina bifida occulta and duplication of the middle phalanx of the third finger on the left hand. Comparative analysis of the present patient and previously reported cases with STAG2 variants suggested that intellectual disability, brain abnormalities, dysmorphic features and skeletal anomalies are the core clinical features of STAG2-related disorders. Furthermore, familial PKD was observed in the proband, mother, aunt and grandmother, confirming an autosomal dominant inheritance pattern associated with the PKD1 variant. In summary, the present report identified a novel de novo STAG2 variant associated with multisystem congenital malformations and a novel familial PKD1 variant causing ADPKD, expanding the genetic and phenotypic spectrum of these disorders. The present findings highlight the utility of WES in diagnosing complex genetic conditions. Barth syndrome is a multisystem disorder characterized in affected males by cardiomyopathy, neutropenia, skeletal myopathy, and prepubertal growth delay; however, not all features may be present in an affected male. Cardiomyopathy, which is almost always present before age five years, is typically dilated cardiomyopathy with or without endocardial fibroelastosis or left ventricular noncompaction; hypertrophic cardiomyopathy can also occur. Heart failure is a significant cause of morbidity and mortality; risk of arrhythmia and sudden death is increased. Neutropenia is most often associated with bacterial infections and aphthous ulcers, pneumonia, and sepsis. Skeletal myopathy predominantly affects the proximal muscles, and results in delays in development of early motor skills. Prepubertal growth delay is followed by a postpubertal growth spurt with remarkable "catch-up" growth. Heterozygous females who have a normal karyotype are asymptomatic and have normal biochemical studies. The diagnosis of Barth syndrome is established in a male proband with suggestive findings and either an increased monolysocardiolipin-to-cardiolipin ratio (if available) or a hemizygous pathogenic variant in TAFAZZIN (formerly TAZ) identified by molecular genetic testing. The diagnosis of Barth syndrome is usually established in a female proband with suggestive clinical findings and a heterozygous TAFAZZIN pathogenic variant identified by molecular genetic testing. Targeted therapy: Elamipretide is indicated for the improvement of muscle strength in individuals with Barth syndrome. Treatment of manifestations: Standard treatment of cardiac issues include: (1) for cardiac arrhythmia, consideration of antiarrhythmic medications or implantable cardiac defibrillator (ICD); (2) for heart failure, careful fluid and volume management and avoidance of overdiuresis and dehydration, standard heart failure medications, and cardiac transplantation when heart failure is severe and intractable. Interventions for other findings include granulocyte colony-stimulating factor for neutropenia; physical therapy for skeletal muscle weakness; standard treatment for talipes equinovarus and/or scoliosis; feeding therapy and consideration of gastrostomy tube placement for persistent feeding issues; uncooked cornstarch prior to bedtime for hypoglycemia; standard management of developmental delay / intellectual disability. Prevention of secondary complications: Aspirin therapy to prevent clot formation in those with severe cardiac dysfunction and/or marked left ventricular noncompaction; antibiotic prophylaxis to prevent recurrent infections; limit fasting or provide intravenous glucose infusion prior to planned medical procedures; regularly monitor blood potassium concentrations during administration of IV fluids that contain potassium and during episodes of diarrhea; consult with nutritionist and/or gastroenterologist to determine optimal caloric delivery. Surveillance: Monitoring existing manifestations, the individual's response to supportive care, and the emergence of new manifestations requires at least annual electrocardiography with Holter monitor and echocardiography; as-needed electrophysiologic studies to assess for potentially serious cardiac arrhythmia; at least semiannual complete blood count with differential as well as with all febrile episodes; at each visit, measurement of height and weight, clinical assessment of strength, and clinical assessment for scoliosis; every three to five years during childhood, formal assessments of developmental progress and educational needs. Agents/circumstances to avoid: Prolonged fasting, use of rectal thermometers in those with neutropenia, and use of succinylcholine. Although growth hormone is typically not indicated as most affected males will attain normal stature by adulthood, recommendations about use of human growth hormone may vary based on endocrinology testing and recommendations. The muscular involvement in Barth syndrome may increase the risk for malignant hyperthermia compared to the general population. Evaluations of relatives at risk: Molecular genetic testing (if the TAFAZZIN pathogenic variant in the family is known) or monolysocardiolipin-to-cardiolipin ratio testing (if the TAFAZZIN pathogenic variant in the family is not known) of male sibs of a proband and male relatives in the maternal lineage is appropriate to identify as early as possible those who would benefit from initiation of treatment and preventive measures. Barth syndrome is inherited in an X-linked manner. If the mother of the proband has a TAFAZZIN pathogenic variant, the chance of transmitting it in each pregnancy is 50%. Males who inherit the pathogenic variant will be affected. Females who inherit the pathogenic variant will be heterozygotes. Heterozygous females typically do not manifest the disease. Affected males transmit the TAFAZZIN pathogenic variant to all of their daughters and none of their sons. If the TAFAZZIN pathogenic variant has been identified in an affected family member, identification of female heterozygotes and prenatal/preimplantation genetic testing for Barth syndrome are possible.

The X-linked syndromic intellectual developmental disorder-35 (MRXS35; OMIM#300998) is caused by variants in the RPL10 gene (OMIM*312173) on chromosome Xq28. Patients with MRXS35 mainly present with intellectual disability (ID), psychomotor development delay, speech delay, short stature, craniofacial anomalies, hypotonia, seizures, gastrointestinal problems, genitourinary anomalies, cardiac anomalies, eye defects, and hearing loss. Herein, we are the first to report two unrelated Chinese patients with the same novel hemizygous missense RPL10 gene variant. Two male patients from two different families were admitted to the hospital for genetic counseling. In the first months of life, both newborns presented with congenital laryngeal stridor, feeding difficulties, neonatal pneumonia, neonatal hypoglycemia, dysmorphic features, and bilateral cryptorchidism. At his last clinical evaluation at 9 years of age, case II presented with ID, speech delay, short stature, and craniofacial anomalies. Whole-exome sequencing identified the same hemizygous missense RPL10 gene variant (NM_006013.5:c.347G>A, p.Arg116Gln) in each patient, inherited from their respective mothers. The functional analysis of this variant in vitro demonstrated that this missense RPL10 gene variant (c.347G>A) reduced the mRNA expression of the RPL10 gene, thereby decreasing synthesis of the RPL10 protein. Our in vitro functional analysis indicated a loss-of-function effect of RPL10 gene variants.

Glycerol kinase deficiency is an X-linked disorder and can occur in isolation or combined as part of the Xp21 continuous gene deletion syndrome. We report the first offspring of a non-consanguineous couple with this contiguous gene deletion syndrome. There was a family history of short stature and learning difficulties, and a personal history of two hospitalizations due to prostration, hypoglycemia, and metabolic acidosis, the first of which occurred at six months of age. The patient was referred to a neurodevelopment consultation due to a global developmental delay detected at two years of age and a genetic consultation at four years old. The array comparative genomic hybridization study identified a maternally inherited hemizygous deletion of the Xp21 region of approximately 6.08 Mb that included both Duchenne muscular dystrophy and glycerol kinase genes, confirming the diagnosis. The patient was referred to metabolic and neurology consultations. Motor examination revealed a waddling gait when running, calf hypertrophy, and a positive Gower's sign. Laboratory evaluation was notable for elevated creatine kinase, hyperglyceroluria, pseudohypertriglyceridemia, and increased transaminases. The patient had a normal adrenocorticotropic hormone stimulation test and normal aldosterone and renin levels. Currently, he has a multidisciplinary team follow-up, including therapies. He maintains deflazacort therapy and follows a nutrition plan based on a fat-restricted diet and avoidance of prolonged fasting to prevent further metabolic crises. This case highlights the importance of identifying the exact genetic defects, in addition to a global picture of symptoms. In our case, it was possible to diagnose complex kinase deficiency along with Duchenne muscular dystrophy. Consequently, it was optimal for multi-profile medical care accompanied by an adequate nutritional plan.

49,XXXXY is a rare sex chromosome aneuploidy with an estimated incidence of 1 in 85,000-100,000 newborn males. Individuals with this syndrome exhibit variable clinical manifestations, typically including developmental delay, intellectual deficits, hypogonadism, and distinctive facial features such as ocular hypertelorism, epicanthic folds, a flat nasal bridge, prognathism, folded-over ears, and a short neck. Unlike patients with Klinefelter syndrome, they are often short in stature. Cornelia de Lange syndrome (CdLS) is an unrelated rare disorder with an incidence of 1 in 10,000-30,000 live births, affecting both sexes. CdLS shares overlapping features with 49,XXXXY, including intellectual deficits and hypogonadism. However, it also presents with unique facial characteristics, such as synophrys, thick or highly arched eyebrows, low-set ears, upturned nasal tips, long eyelashes, and microcephaly. CdLS is a clinically and genetically heterogeneous condition, with severe cases involving congenital malformations including limb anomalies, and milder cases showing only subtle facial dysmorphism. Both syndromes may also involve cardiac and renal anomalies. We report the first documented concurrence of 49,XXXXY and X-linked CdLS, emphasizing the challenges in diagnosis and the phenotypic overlap between these two rare syndromes, and propose a theoretical mechanism for the co-occurrence.