ASXL3-related disorder, also known as Bainbridge-Ropers syndrome (BRPS), is a neurodevelopmental condition first described by Bainbridge et al. and characterized by delayed psychomotor development, learning difficulties, characteristic craniofacial features, hypotonia, behavioral problems, and feeding problems. It is associated with heterozygous truncating pathogenic variants in the ASXL3 gene, located at chromosomal region 18q12.1. In this study, exome sequencing was performed in a 7-month-old male and a 4-year-old female patient who presented with unexplained developmental delay. De novo truncating variants in the ASXL3 gene were identified in both patients. Genetic analysis revealed that Patient 1 had a canonical splice-site likely pathogenic variant in the ASXL3 gene c.3039 + 1G > A. Patient 2 had a pathogenic variant in the ASXL3 gene c.1864_1867dup; p.Thr623Metfs∗25. We compared the patients' physical examination findings, clinical characteristics, and genetic results with those reported in the literature. This case report emphasizes the phenotypic spectrum of this disorder and describes a variant that, to our knowledge, has not been previously reported in the literature.
Mosaicism for both a ring chromosome and Robertsonian translocation is a rarely reported cytogenetic phenomenon. We describe a case referred for testing following abnormal noninvasive prenatal screening for trisomy 13. Prenatal chromosomal microarray (CMA) testing identified a mosaic 3.6-Mb terminal loss in 13q34, which was confirmed by postnatal CMA. At birth, the phenotype included a small head circumference (3rd percentile) and a patent ductus arteriosus. Conventional chromosome analysis identified mosaicism of two abnormal cell lines, one containing der(13;21)(q10;q10) and the other containing r(13)(p11.2q33). This case demonstrates the utility of conventional chromosomal analysis following an abnormal CMA result.
Background:Germline genetic testing is integral to precision oncology in prostate cancer (PCa), particularly for men with pathogenic or likely pathogenic (P/LP) BRCA1/2 variants, where results have therapeutic and hereditary implications. However, data from the Middle East remain limited regarding real-world implementation of genetic counseling and its influence on family communication and cascade testing. Aim:To describe the role and challenges of genetic counseling for BRCA2-associated PCa in Omani patients, focusing on family communication, risk awareness, and cascade testing uptake. Methods:This descriptive, retrospective case series included nine men with PCa carrying P/LP BRCA2 variants identified between September 2021 and December 2025. Clinical and genetic data were extracted from electronic records, and genetic counseling documentation was reviewed for family history, psychosocial context, communication patterns, and cascade testing. Quantitative data were summarized descriptively. Qualitative content analysis of counseling records identified recurring sociocultural and communication-related factors. Findings and Discussion:Patients were aged 60-76 years at the time of PCa diagnosis, with varied educational backgrounds and disease stages, and all carried BRCA2 variants. Awareness of diagnosis differed, with some patients partially informed or unaware. These findings underscore the pivotal role of genetic counseling in translating BRCA2 molecular results into actionable strategies for patients and families. Family-mediated protective nondisclosure and decision-making were prominent. Cascade testing uptake was higher in families with younger or medically informed relatives and lower where stigma or fear prevailed. Conclusion:In this single-center Omani case series, effective counseling for BRCA2-associated PCa required navigating complex cultural dynamics related to family-mediated communication and decision-making. Integrating culturally sensitive, family-centered genetic counseling into routine oncology care may save lives by empowering families to act earlier on inherited risk.
Malan syndrome is a rare overgrowth disorder caused by deletions or pathogenic variants in the NFIX gene. Here, we present the case of a Japanese male infant with Malan syndrome, which was caused by a novel frameshift variant resulting from an eight-base insertion in Exon 2 of the NFIX gene. Echocardiography revealed dilatation of the pulmonary artery without hemodynamic abnormalities. Malan syndrome shares many clinical features with Sotos syndrome, including overgrowth, macrocephaly, developmental delay, and intellectual disability. Therefore, molecular genetic testing is required for diagnosis. Pathogenic variants in the NFIX gene have also been reported in individuals with Marshall-Smith syndrome. Some individuals exhibit phenotypic overlap between Malan syndrome and Marshall-Smith syndrome. Our patient was diagnosed with Malan syndrome because he had a frameshift variant in Exon 2, resulting in haploinsufficiency, and exhibited macrocephaly, but not proptosis or micrognathia. To our knowledge, this is the second reported case in the literature of concomitant pulmonary artery dilatation in Malan syndrome.
Background:Pallister-Killian syndrome (PKS) is a rare disorder caused by tissue-limited mosaicism tetrasomy of chromosome 12p. Affected newborns show a typical dysmorphic pattern: macrosomia, coarse facies, hypertelorism, small nose with long philtrum, V-shaped upper lip, low set ears, frontotemporal alopecia, and patchy pigmentary skin and hair anomalies. Seizures and developmental delay, cardiac defects, diaphragmatic hernia, and renal/anal malformations may be associated. Case:Here, we report the case of a newborn with multiple congenital malformations, later diagnosed with PKS. Conclusions:Phenotypic and cytogenetic variability of PKS, together with the lack of correlation between tetrasomic cells' proportion and disease severity, may be challenging for diagnosis. Therefore, a detailed physical examination is mandatory for early clinical suspicion and to guide further investigations. The usefulness of array-CGH performed on peripheral blood should also be emphasized as a sensitive diagnostic tool.
Introduction:Nonimmune hydrops fetalis (NIHF) has numerous etiologies, the most common of which are cardiac anomalies and fetal infection. However, genetic disorders are also being increasingly recognized as a cause of NIHF. Here, we report a case of a neonate presenting with polyhydramnios, NIHF, structural heart disease, and diaphragmatic defect who was found to have a previously unreported mutation in the KMT2D gene. Case Presentation:A female neonate with antenatally detected NIHF was born at 35 weeks of gestation via cesarean section. At birth, she was noted to have dysmorphic features, scoliosis, and a single umbilical artery. Further investigations revealed a left-sided obstructive cardiac lesion and a right-sided Morgagni hernia. She required invasive ventilation, inotropes, and prostaglandin E1 for preductal coarctation of the aorta with hypoplastic left heart syndrome. Genetic analysis was warranted due to multiple anomalies in the neonate. Whole exome sequencing (WES) showed a previously unreported truncating mutation in the KM2TD gene, confirming the diagnosis of Kabuki syndrome type 1. Conclusion:Kabuki syndrome is rare, and its presentation with hydrops is extremely rare. Our case presented with polyhydramnios, antenatal hydrops, hypoplastic left heart, right-sided Morgagni hernia, and scoliosis with a novel mutation, thus potentially expanding the genotype-phenotype spectrum of this syndrome. This case highlights that a pediatrician should have a high index of suspicion for inherited genetic syndromes in a case of nonimmune hydrops with multiple congenital anomalies. Genetic tests are valuable for identifying rare syndromes and novel mutations.
Male infertility can be caused by various microdeletions of the azoospermia factor (AZF) gene, some of which require sperm retrieval techniques for treatment. Yet, the likelihood of success with such techniques depends partly on the affected AZF gene segment. For patients with select AZF microdeletions, other options such as in vitro fertilization, sperm donation, and adoption may be more appropriate. We present a case about a 32-year-old male diagnosed with infertility due to azoospermia from a complete AZFb + c deletion, which is unlikely to be successfully treated with sperm retrieval techniques. The goal of this case report is to highlight the significance of earlier diagnosis of AZF microdeletions in infertile males to facilitate earlier genetic counseling and pursuit of the most appropriate intervention.
Complete androgen insensitivity syndrome (CAIS) is caused by pathogenic variants in the androgen receptor (AR) gene that lead to a phenotypically female appearance in XY individuals. It is almost always inherited as an X-linked recessive condition. Here, we present two sisters with different clinical courses. AR gene sequencing revealed identical hemizygous pathogenic variants in both sisters but not in the mother. This rare occurrence of germline mosaicism is the first described in CAIS. Germline mosaicism should be considered when “de novo” AR gene variants are identified. Despite the low recurrence risk, counseling would be beneficial to families so they can make well-informed prenatal and reproductive plans.
Snijders Blok–Campeau syndrome is caused by a heterozygous CHD3 pathogenic variant, and characterized by features including macrocephaly, speech delay, hypotonia, and joint laxity. In the hereby-presented case, a Japanese girl with Snijders Blok–Campeau syndrome displayed bilateral middle finger camptodactyly and early-onset scoliosis, beyond the characteristic symptoms such as intellectual disability, facial abnormalities, macrocephaly, and hypotonia due to a recurrent CHD3 pathogenic variant. This case expands our knowledge of the phenotypic spectrum of Snijders Blok–Campeau syndrome.
We present a unique case of an infant born with both a microduplication of 22q11.2 and SNRPB gene mutations suggestive of cerebro-costo-mandibular syndrome (CCMS). Microduplications of 22q11 are known to present with a variety of phenotypes ranging from asymptomatic to significant physical and mental health challenges. CCMS is a rare autosomal dominant condition caused by a mutation in the SNRPB gene and typically presents with posterior rib malformations and branchial arch deformities. There have been less than 100 reported cases of CCMS in the literature, and this may be the first documented case of a patient with both CCMS and a 22q11 microduplication.
Childhood apraxia of speech (CAS) is characterized by motor discoordination in the speech domain and also in fine and gross motor systems, implicating the early developing cerebellum. Comorbidity with autism spectrum disorder (ASD) and other neurodevelopmental conditions has been observed. The genetic etiology is highly heterogeneous. Here, we present three unrelated individuals with CAS and concomitant fine and gross motor involvement but different genetic variants of interest. The DNA of the cases and their parents underwent exome sequencing and variant filtering. Using publicly available data, the genes of interest derived from the variants were investigated for expression rates in the early developing brain. Known and putative protein-protein interactions among the genes of highest confidence were identified. Of 28 variants in 28 different genes, variants with highest confidence were situated in FOXN4, LAMA5, LAMB1, LRRK2, and USP17L2. High gene expression rates in the developing cerebellum were observed for LAMA5 and LAMB1. These genes encode the α5 and β1 subunits, respectively, of the heterotrimeric extracellular laminin-511 complex, a major component of the basal membrane in many tissues. Network analysis of the five high-confidence genes required expansion with only one additional gene, CDK6, to arrive at a fully connected network. The addition of four genes and inclusion of transcriptional regulation as an additional edge type allowed connecting all 28 genes of interest to arrive at a dense connectome with 32 nodes and 73 edges, representing a network enrichment with p value of < 0.001, suggesting that our network has significantly more interactions than expected under random conditions. We conclude that high levels of genetic heterogeneity converge on a functional gene network governed by stimulation of cells through laminin-511 with shared direct or regulatory expression in the developing cerebellum and phenotypic overlaps of CAS, ASD, and other neurodevelopmental disorders.
Background:Hereditary myopathy with early respiratory failure (HMERF) is a rare autosomal dominant disorder caused by TTN variants. COL4A5 mutations are linked to X-linked Alport syndrome. Case Presentation:A 34-year-old male developed progressive lower limb weakness, gait disturbance, nocturnal hypoventilation, and calf hypertrophy. Family history revealed similar symptoms in his mother and sister. Examination showed absent reflexes; MRI demonstrated muscle atrophy and fatty replacement; needle electromyography (EMG) was performed and showed findings consistent with advanced myopathy; however, it was not used as a primary diagnostic tool. Whole-exome sequencing identified a pathogenic TTN variant (c.95126C > G, p.Pro31709Arg), confirming HMERF. A hemizygous COL4A5 variant (c.4891C > T, p.Arg1631Cys) was also detected but lacked clinical correlation. Discussion and Conclusion:This case illustrates a classic HMERF phenotype confirmed genetically, with an incidental COL4A5 variant of uncertain significance. It underscores the importance of genomic testing in atypical neuromuscular presentations and the need for cautious interpretation of incidental findings.
Desbuquois dysplasia Type 1 (DBQD1) is an extremely rare autosomal recessive skeletal dysplasia characterized by severe short stature, joint laxity, distinct facial dysmorphism, and advanced carpotarsal ossification. Here, we report the first Thai patient diagnosed with classical lethal DBQD1. A 38-week male infant presented with multiple dysmorphic features, micromelia, joint dislocations, narrow thorax, and respiratory insufficiency leading to death at seven months of age. Radiographic findings revealed hallmark features, including a "Swedish key" appearance of the proximal femur and characteristic hand and foot anomalies. Whole exome sequencing identified compound heterozygous missense variants of c.505G > A (p.Asp169Asn) and c.1028G > T (p.Gly343Val) in the CANT1 gene. The 3D structural modeling revealed that both variants reside in conserved regions, with predicted effects on calcium binding and protein folding, resulting in impaired enzymatic function and proteoglycan synthesis. Genetic counseling was provided to the family, and prenatal or preimplantation genetic diagnosis was discussed as an option for future pregnancies. Our report expands the mutational spectrum of the CANT1 gene, contributing to a better understanding of DBQD1's clinical and molecular presentation, particularly in Southeast Asian populations.
Background:Mitochondrial DNA depletion syndrome 13 (MTDPS13) is an autosomal recessive disorder presenting in early infancy with encephalopathy, hypotonia, lactic acidosis, and severe global developmental delay. Patient-derived cells typically exhibit impaired mitochondrial oxidative phosphorylation and a marked reduction in mitochondrial DNA (mtDNA) copy number. Case Report:We report the case of a male preterm neonate born at 31 + 3 weeks of gestation following a pregnancy marked by severe polyhydramnios. At birth, his weight was 1400 g. Physical examination revealed dysmorphic features, redundant and lax skin, and generalized muscular hypotonia. Laboratory investigations showed marked lactic acidosis associated with lactic aciduria, ketonuria, and urinary biomarkers indicating activation of preoxidative phosphorylation biochemical pathways to sustain ATP production. Echocardiography demonstrated mild, early-onset hypertrophic cardiomyopathy. The Exome Analysis Clinical and Biochemical Markers: The exome analysis, performed within the first week of life, highlighted a pathogenic variant in homozygous state of FBXL4 gene (c.1648_1649delGA), which led to the diagnosis of MTDPS13. In this clinical contest, a ketogenic diet (KD) was started with a daily caloric intake of 120 kcal/kg and an initial ketogenic ratio of 1:1. These intakes were administered both with a parenteral nutrition and continuous nasogastric tube feeding and were gradually increased and adapted on a day-by-day basis according to lactic acidosis, growth increase, and common metabolic parameters such as glucose, electrolytes, creatinine, and blood urea nitrogen. After 3 days of this treatment approach, a significant reduction in lactate levels and improvement in acid-base balance and growth trend were observed along with clinical and cardiovascular parameters. At discharge from neonatal intensive care unit, the KD was continued at home and during follow-up. The infant showed stability in the clinical and biochemical markers. Conclusions:This is the first documented report of the use of a KD in a preterm neonate with this mitochondrial disorder during the early days of life. Prompt genetic confirmation and early initiation of KD may enable a more targeted and effective management of MTDPS within the neonatal intensive care setting.
Trisomy 8 mosaicism (T8M) syndrome is a rare aneuploidy condition affecting 1/25,000-50,000 live births. Affected individuals have highly variable phenotypes from very mild dysmorphism to severe structural anomalies caused by chromosomal mosaicism and possibly undetected molecular aberrations. The utilization of chromosome microarray analysis (CMA) and exome sequencing (ES) in clinical laboratories enable the identification of genomic copy number imbalances and pathogenic gene variants. We presented one patient with a double aneuploid mosaic pattern of Monosomy X and Trisomy 8 for a compound phenotype of Turner syndrome (TS) and T8M syndrome, the second patient with T8M and a mosaic pathogenic variant in the PTEN gene detected by ES, and the third patient with typical phenotypic constellation of malformations with no other genetic aberrations detected by CMA and ES. Classification of mosaic findings was provided using a recommended six-attribute scheme. Review of the literature summarized cases of T8M with concomitant molecular defects of a deletion at 22q11.2 and pathogenic variants in the SALL1, RECQL4, NF1, CASK, and PAH genes. These observations indicated that integrated cytogenetic and genomic analyses should be offered to patients with phenotypic abnormalities outside the spectrum of the T8M syndrome for comprehensive laboratory diagnosis and clinical management.
Background:Hypokalemic periodic paralysis (HypoPP) is a rare skeletal muscle channelopathy, most often caused by mutations in CACNA1S or SCN4A. Most pathogenic CACNA1S mutations affect arginine residues in S4 voltage-sensor domains, but other variants remain poorly understood. Case Presentation:I describe a 30-year-old Caucasian woman with recurrent paralytic episodes and hypokalemia (2.1-2.3 mmol/L), triggered by stress and carbohydrate-rich meals. Genetic testing revealed heterozygosity for CACNA1S c.3727C > G (p.Leu1243Val), a variant of uncertain significance not previously associated with pathogenicity. Her phenotype was consistent with HypoPP. Treatment with spironolactone and acetazolamide reduced episode frequency, although the latter caused intolerable side effects, particularly tachypnea; she was later approved for dichlorphenamide. During one hospitalization, she also developed transient hypophosphatemia and hypokalemia, consistent with her HypoPP picture. Kidney function and imaging were normal. Family history revealed electrolyte disturbances in her grandfather. Conclusions:This case highlights a possible genotype-phenotype link involving CACNA1S p.Leu1243Val. Continued reporting of such cases is essential for variant reclassification and for improving recognition of metabolic shifts during HypoPP attacks.
Gastric adenocarcinoma and proximal polyposis of the stomach (GAPPS) is a rare autosomal dominantly inherited gastric cancer syndrome that is characterized by fundic gland polyposis of the stomach (> 100) and an increased risk of gastric cancer. The genetic cause is recognized as a pathogenic variant in the promotor 1B of the APC gene. Presently, there are no established clinical criteria, and current guidelines are based on limited evidence. In this report, we identified two families with GAPPS. Family I had a family history of gastric cancer, and we identified seven family members with GAPPS. The diagnosis was verified by endoscopic findings of polyposis and genetic analysis identifying a variant in the promotor 1B of the APC gene, NM_001127511.3: c.-191T > C. In Family II, the same pathogenic variant, NM_001127511.3: c.-191T > C, was detected as an incidental finding in a 61-year-old patient with hepatocellular carcinoma, clear cell renal carcinoma, and small cell lung cancer. An esophagogastroduodenoscopy (EGD) at the age of 59 had revealed only one small fundic polyp. This is the first report of patients with GAPPS from Denmark, and it emphasizes the variable phenotypic expression and subsequently the difficulty of surveillance and genetic counseling in these patients and their families.
Primary ciliary dyskinesia (PCD) is a rare and heterogeneous inherited disease characterized by impaired mucociliary clearance. Patients with PCD typically present with recurrent respiratory infections resulting in the development of bronchiectasis. Even though awareness of the disease has increased over the years, PCD remains underdiagnosed. We here present a case of a newly diagnosed middle-aged female found to have a previously undescribed variant of the disease-associated DNAAF3 gene.
Primary familial basal ganglia calcification (PFBC), also known as Fahr's disease, is a rare neurodegenerative condition characterized by bilateral calcifications in the basal ganglia and other brain regions. While it predominantly presents in adulthood and is commonly associated with heterozygous mutations, rare homozygous pathogenic variants may lead to severe early-onset manifestations. We present a unique case of PFBC in a 2-month-old female infant who exhibited focal motor seizures shortly after routine immunization. Neuroimaging revealed bilateral basal ganglia calcifications, multifocal cerebral infarcts, and evidence of significant intra-arterial cerebral vasculopathy. Genetic testing confirmed a homozygous pathogenic variant in the SLC20A2 gene (c.1399 C > T) (p.R467∗). Notably, both consanguineous parents were heterozygous carriers of the same mutation. Other family members across two generations also harbored heterozygous variants but were asymptomatic. This case is one of the few reported instances of a homozygous SLC20A2 pathogenic variant and the second to demonstrate intra-arterial vasculopathy in infancy. The clinical spectrum included seizures, hypotonia, poor feeding, and extensive ischemic changes. Despite supportive care and antiepileptic therapy, the patient remained neurologically impaired. This report underscores the importance of considering PFBC in the differential diagnosis of infantile seizures, especially in populations with high rates of consanguinity. It also expands the phenotypic spectrum of SLC20A2-related disease to include infantile stroke due to cerebral vasculopathy. Early diagnosis and genetic counseling are essential for management and family planning.
