Kabuki syndrome (KS) is a rare, multiple congenital anomaly syndrome, characterized by dysmorphic facial features, skeletal anomalies, dermatoglyphic abnormalities, developmental delay, mild-to-moderate intellectual disability, and postnatal growth restriction. KS type 1 (KS1, OMIM 147920) is caused by autosomal dominant pathogenic mutations in KMT2D, and KS type 2 (KS2, OMIM 300867) is caused by X-linked dominant pathogenic mutations in KDM6A. To identify the genetic etiologies in a fetus with increased nuchal translucency (NT) observed by ultrasound at 11+6 weeks of gestation. Chromosomal microarray analysis (CMA) and trio-exome sequencing (trio-ES) were performed on amniotic fluid sample to investigate the potential genetic causes. Sanger sequencing was utilized for validation of the candidate variant. A 28-year-old Chinese pregnant woman was referred for prenatal evaluation due to fetal increased NT (NT = 6.7 mm). CMA yielded a normal result, with no pathogenic or likely pathogenic copy number variants, or mosaicism detected. However, trio-ES identified a novel de novo frameshift mutation (NM_021140.4: c.2429dup (p.Thr811Aspfs*2)) in the KDM6A gene. This variant was classified as pathogenic (PVS1 + PS2_Supporting + PM2_Supporting) based on the American College of Medical Genetics and Genomics guidelines. The fetus was diagnosed with X-linked dominant KS2. The identification of this novel frameshift variant, together with the first report of increased NT as a prenatal feature, enriched both the mutation spectrum and prenatal phenotypic spectrum of KS2. These findings underscore the diagnostic utility of ES for fetuses with increased NT, especially when CMA yields normal results.

Xq28 duplications are a significant cause of X-linked intellectual disability (XLID). While the postnatal features of distal Xq28 duplication syndrome are well characterized, the prenatal phenotypes remain poorly defined due to limited data, posing challenges for genetic counseling. We identified three fetuses carrying 454-558 kb distal Xq28 microduplications through chromosomal microarray analysis (CMA) from 13,084 prenatal cases at our center. The primary indications for diagnosis were abnormal ultrasound findings. Case 1 (male) and case 3 (female) exhibited nasal bone hypoplasia. Case 2 (male) showed increased nuchal translucency (NT) and a persistent right umbilical vein. After genetic counseling, two couples chose to terminate their pregnancies, while one couple continued the pregnancy and delivered a healthy child. Distal Xq28 duplications would present diverse prenatal phenotypes, ranging from normal to abnormal. Skeletal anomalies are the most common prenatal features in symptomatic fetuses with this duplication. Prenatal diagnosis and genetic counseling are essential for providing clinical guidance to the affected families. The correlation between prenatal ultrasound findings and the distal Xq28 duplications requires further investigation in larger cohorts.

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.

Galactosemia is a congenital disorder of carbohydrate metabolism, in which the body is unable to metabolize galactose properly. Coffin-Lowry syndrome (CLS) is characterized by intellectual disability, developmental delay, dysmorphic features, growth retardation, vision and hearing loss, and skeletal changes, which is an X-linked disorder, with males being more severely affected, whereas the clinical findings in females show variability. This case is presented due to the rare concomitance of galactosemia and CLS. A 2-year-old female patient, previously diagnosed with galactosemia, who had good dietary adherence was noticed to have developmental delay, dysmorphic features, nephrolithiasis and recurrent pericardial effusions during follow-up. Further research was carried out to diagnose an underlying second disease. Metabolic tests were inconclusive. Clinical exome sequencing (CES) analysis, revealed a heterozygous c.472C>T p. (Arg158Cys) pathogenic variant in RPS6KA3 (OMIM #300075) and CLS (OMIM #303600) was diagnosed. This case report is a unique summary of a patient with galactosemia who further was diagnosed with CLS that emphasizes the possibility of co-occurrence of rare diseases and highlights the importance of conducting further investigations in patients with unexplained findings in the context of existing metabolic diseases.

Hemizygous variants in the RLIM gene, which is located on chromosome Xq13, cause Tønne-Kalscheuer syndrome (TOKAS). This X-linked recessive disorder is characterized by intellectual disability (ID), global developmental delay, behavioral impairment, gait disturbances, minor facial anomalies, congenital diaphragmatic hernia, skeletal and urogenital abnormalities, including hypogenitalism, micropenis, and cryptorchidism. In this study, we report on a novel, likely pathogenic RLIM variant in a proband, the clinical phenotype of which is consistent with a diagnosis of TOKAS. Whole-exome sequencing (WES) was performed on a genomic DNA (gDNA) sample of the proband to identify the disease-causing variant. Validation and segregation analysis were performed by Sanger sequencing of the proband’s and his mother’s gDNA samples. Computational analysis and protein structure modelling were applied to assess the possible influence of the variant on protein function. A novel missense variant NM_016120.4:c.1721T > A, NP_057204.2:p.(Ile574Asn) in the RLIM gene was identified by the analysis of WES data. Segregation analysis revealed the asymptomatic mother to be a carrier of the familial missense variant, and a highly skewed X chromosome inactivation pattern was observed in this study. The altered residue was determined to be at the interaction interface between E3 ubiquitin ligase RLIM and E2 ubiquitin-conjugating enzymes. The findings provided in this study suggest that the affected residue Ile574 could alter the interactions of the RING domain with the E2 ubiquitin-conjugating enzymes and therefore could influence the ubiquitin-mediated protein regulation pathways. The online version contains supplementary material available at 10.1186/s12887-025-06194-3. Kabuki syndrome (KS) is characterized by typical facial features (long palpebral fissures with eversion of the lateral third of the lower eyelid; arched and broad eyebrows; short columella with depressed nasal tip; large, prominent, or cupped ears), minor skeletal anomalies, persistence of fetal fingertip pads, mild-to-moderate intellectual disability, and postnatal growth deficiency. Other findings may include: congenital heart defects, genitourinary anomalies, cleft lip and/or palate, gastrointestinal anomalies including anal atresia, ptosis and strabismus, and widely spaced teeth and hypodontia. Functional differences can include: increased susceptibility to infections and autoimmune disorders, seizures, endocrinologic abnormalities (including isolated premature thelarche in females), feeding problems, and hearing loss. The diagnosis of KS is established in a proband of any age with a history of infantile hypotonia, developmental delay, and/or intellectual disability AND one or both of the following: Typical dysmorphic features (long palpebral fissures with eversion of the lateral third of the lower eyelid, and ≥2 of the following: arched and broad eyebrows with the lateral third displaying notching or sparseness; short columella with depressed nasal tip; large, prominent, or cupped ears; persistent fingertip pads). A heterozygous pathogenic variant in KMT2D or a heterozygous or hemizygous pathogenic variant in KDM6A. Treatment of manifestations: Thickened feedings and positioning after meals to treat gastroesophageal reflux; gastrostomy tube placement if feeding difficulties are severe. If cognitive difficulties are evident, psychoeducational testing and special education services to address the individual child's needs. Evaluation by a developmental pediatrician or psychiatrist if behavior suggests autism spectrum disorders. Standard anti-seizure treatment. Standard treatment for hyperinsulinism. Prevention of secondary complications: Prophylactic antibiotic treatment prior to and during any procedure (e.g., dental work) may be indicated for those with specific heart defects. Surveillance: Monitor height, weight, and head circumference at each well-child visit and, at a minimum, yearly. Developmental milestones should be followed with each well-child visit. Monitor vision and hearing on a yearly basis. KMT2D-related KS is inherited in an autosomal dominant manner; KDM6A-related KS is inherited in an X-linked manner. Autosomal dominant inheritance: The proportion of KS caused by a de novo KMT2D pathogenic variant is unknown but is likely high based on clinical experience. In the rare case that a parent of the proband is affected, the risk to the sibs is 50%. X-linked inheritance: If the mother of the proband has a KDM6A 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 heterozygous and may have features of KS. Once the causative pathogenic variant has been identified in an affected family member, prenatal and preimplantation genetic testing for KS are possible.