Molecular Syndromology最新文献

Introduction: Bardet-Biedl syndrome (BBS) is a genetically heterogeneous, multisystemic ciliopathy, whereas autism spectrum disorder (ASD) is a neurodevelopmental disorder characterized by deficits in social interaction and restricted, repetitive behaviors. While both conditions are independently associated with genetic etiologies, their co-occurrence is exceptionally rare. To date, no prior report has confirmed such co-occurrence through molecular genetic analysis.

Case presentation: We report a 4-year-old male diagnosed with both BBS type 10 and ASD. Whole exome sequencing (WES) revealed a homozygous pathogenic variant in the BBS10 gene and a novel heterozygous intronic variant in the OGT gene, classified as a variant of uncertain significance. Clinically, the patient exhibited features consistent with both disorders, including retinal degeneration, polydactyly, renal anomalies, hypotonia, and ASD-specific behavioral patterns.

Conclusion: This case represents the first genetically confirmed co-occurrence of BBS10 and ASD. The identification of a potentially contributory non-coding variant in the OGT gene provides novel insight into the shared genetic and pathophysiological mechanisms underlying ciliopathies and neurodevelopmental disorders. The findings emphasize the importance of dual diagnostic consideration in complex pediatric cases and demonstrate the value of genomic analysis in revealing rare genetic overlaps.

Introduction: Heterozygous variants in MAP3K20 have been implicated in a recently identified syndromic form of ectodermal dysplasia, distinguished by a unique combination of ectrodactyly, craniosynostosis, bilateral sensorineural hearing loss, and skeletal anomalies such as transverse limb defect, and brachydactyly.

Case presentation: We present an 11-year-old male with ectrodactyly, ectodermal dysplasia, bilateral sensorineural hearing loss, and cutaneous syndactyly in both hands. A de novo heterozygous variant, c.837_839del p.(Asn279del), in MAP3K20 was identified in his whole exome sequencing.

Conclusion: The results of this study emphasize the critical role of MAP3K20 as a key gene in conditions involving ectrodactyly, craniosynostosis, bilateral sensorineural hearing loss, ectodermal features, transverse limb defect, and brachydactyly. We highlight the importance of prioritizing the recurrent p.(Asn279del) variant in genetic testing for affected individuals. Furthermore, we propose an acronym for this dominant disorder caused by the MAP3K20 gene variants: DECES (Dominant/Deafness, Ectodermal Dysplasia, Craniosynostosis, Ectrodactyly, Skeletal anomalies).

Introduction: Congenital heart defects (CHD) affect approximately 10-12 per 1,000 newborns globally, and they can be divided into simple cardiac defects or severe and complex ones. Its etiology derives from environmental and genetic causes, with 20-30% of cases being genetic conditions ranging from alterations such as aneuploidies, monogenic defects, and copy number variations (CNVs). Even with the severity of this condition, many patients remain with an uncertain diagnosis. This study aimed to evaluate patients with CHD who are still undiagnosed but have already undergone genetic testing and evaluation and provide a guideline that can be followed in third-world countries to make CHD diagnostics faster and easier.

Method: DNA was extracted from all patients included; first the samples were analyzed with the P311 multiplex ligation-dependent probe amplification (MLPA) kit specific to CHD, and the patients that remain undiagnostic were analyzed with the P245 MLPA kit for microdeletions.

Results: CNVs were identified in 36% of the patients, representing a high detection rate.

Conclusion: The patient selection and prior clinical evaluation may explain our high detection rate, as much as the karyotype and fluorescent in situ hybridization normal results used for screening, combined with using two MLPA kits for detection.

Introduction: Bardet-Biedl syndrome (BBS) is a rare autosomal recessive disorder classified as a multisystem nonmotile ciliopathy, primarily characterized by retinal cone-rod dystrophy, central obesity, postaxial polydactyly, cognitive impairment, kidney disease, and abnormalities of hypogonadism and genitourinary.

Case presentation: A fetus presenting with enlarged kidneys and enhanced echogenicity was identified during a prenatal screening at 17 weeks of gestation. Genetic analysis of the fetus was performed using chromosomal microarray analysis (CMA) and clinical exome sequencing (CES). The prenatal assessment yielded notable results in the fetus, with CMA and CES analysis detecting a compound heterozygous variant in the BBS7 gene and a substantial deletion in the chromosomal region 4q26q27. Subsequent autopsy findings corroborate the presence of postaxial polydactyly, bilateral renal enlargement, and an accessory auricle in the fetus.

Conclusions: Our study expands the range of phenotypes associated with BBS to include bilateral accessory auricle, as well as broadens the spectrum of variants linked to BBS. Our findings support the significant contribution of copy number variants to BBS, offering clinicians valuable insights for diagnosing the condition, particularly in prenatal settings.

Introduction: Hyperphosphatasia with mental retardation syndrome (HPMRS) is characterized by intellectual impairment, seizures, hypotonia, facial dysmorphism, and elevated serum alkaline phosphatase (ALP) level. HPMRS has been linked to mutations in several genes including PGAP2 and PGAP3. Here, we report 2 patients of HPMRS3 and HPMRS4 and highlight the genetic and phenotypic diversity of this disorder.

Case reports: Patient 1, a 1-year-old male with developmental delay, generalized tonic-clonic seizures, and dysmorphic facial features, was found to have a pathogenic variant in the PGAP3 gene. Patient 2, a 1-year-old female with seizures, hypotonia, joint hypermobility, and facial dysmorphism, was found to have a pathogenic variant in the PGAP2 gene. Both patients exhibited elevated ALP levels. Brain MRI of patient 1 revealed periventricular hyperintense signal foci, while patient 2 showed cerebral atrophy and basal ganglia diffusion restriction.

Discussion: HPMRS3 and HPMRS4 share clinical features including elevated ALP levels, developmental delay, seizures, and facial dysmorphisms. Although joint hypermobility is not a common feature of HPMRS3, it was observed in our patients. Both patients responded well to high-dose pyridoxine, suggesting a potential therapeutic benefit for seizure management. This report expands the understanding of HPMRS by presenting novel genetic findings and providing insights into the clinical presentation of PGAP2- and PGAP3-related conditions.

Introduction: Hypoparathyroidism, sensorineural deafness, and renal dysplasia (HDR) syndrome is caused by haploinsufficient GATA3 variants. Renal disease is present in 72% of patients with HDR syndrome, with a widely variable age of onset and rate of progression. Overall prognosis is primarily dependent upon the severity of renal disease. Four patients have been previously reported to have kidney transplants due to HDR syndrome, but there are minimal data describing transplant outcomes. We describe a case of a 74-year-old male with HDR syndrome receiving a living related renal transplant lasting 27 years.

Case presentation: A 74-year-old male with genetically confirmed HDR syndrome due to a pathogenic c.608_609del (p.Gly203Glufs*100) variant in GATA3. He developed hearing loss as an adolescent and was diagnosed with end stage renal disease at age 46. He had a living donor kidney transplant at age 47 that was well tolerated until age 73, and he is now listed for a repeat transplant.

Discussion: This individual previously had a clinical diagnosis of Alport syndrome, but the presence of congenital symptoms in other family members suggested an alternative diagnosis. In addition to highlighting discrepancies between Alport syndrome and HDR syndrome, this case establishes that long-term successful renal outcomes are possible in HDR syndrome. Current limited evidence suggests kidney transplantation should be readily offered to individuals with end-stage renal disease due to HDR syndrome.

Introduction: The Crumbs homolog-2 (CRB2)-related syndrome is an extremely rare genetic disorder characterized by congenital hydrocephalus, steroid-resistant nephrotic syndrome, and cardiac anomalies. It is caused by biallelic variants in the CRB2 gene.

Case presentation: Herein, 2 new patients are presented including congenital hydrocephalus, nephrotic syndrome, scimitar syndrome, and severe cardiac anomalies. CRB2-related syndrome was considered with the present clinical findings and whole exome sequencing revealed three novel variants in CRB2 gene. Microcephaly, ventricular hypertrophy, anomalous pulmonary venous return, pulmonary sequestration, and thymus hypoplasia were presented only in the current patients. Variants in exon 2 (c.335G>A, p.Cys112Tyr) and intron 2 (c.419-2A>G) were reported only in the presented report. In addition, the first likely pathogenic splice-site variant was reported in this report.

Conclusion: Accurate diagnosis is crucial for increasing clinical awareness and offering genetic counseling to affected families.

Introduction: Cerebrotendinous xanthomatosis (CTX) is a rare, autosomal recessive lipid storage disorder characterized by the accumulation of cholesterol and cholestanol in various tissues. It is caused by pathogenic variants in the CYP27A1 gene, which encodes the mitochondrial enzyme sterol 27-hydroxylase.

Case presentation: Here, we present an 8-year-old boy with attention-deficit/hyperactivity disorder, born to non-consanguineous parents. He was referred to our center for CYP27A1 gene analysis and genetic counseling, following the identification of a homozygous deletion in exon 6 of the CYP27A1 gene in his mother. His plasma cholestanol levels were also elevated, supporting a diagnosis of CTX. The proband's father had a history of epilepsy and mild intellectual disability. Genetic analysis of the father revealed a novel heterozygous p.(Glu170Valfs*16) variant in the CYP27A1 gene. Based on these findings, the proband was found to carry a compound heterozygous variant in CYP27A1, confirming the molecular diagnosis of CTX. After genetic counseling, treatment with chenodeoxycholic acid (CDCA) was initiated. Plasma cholestanol levels normalized, and some clinical symptoms showed improvement after 2 months of treatment.

Conclusions: Early genetic screening of presymptomatic family members is critical, as timely initiation of CDCA therapy can prevent or significantly attenuate the clinical progression of CTX.

[This corrects the article DOI: 10.1159/000545585.].

Introduction: Zhu-Tokita-Takenouchi-Kim (ZTTK) syndrome is a rare multisystemic congenital disorder caused by SON gene variants. This study aimed to present the results of whole exome sequencing, and describe some rare findings observed in the proband.

Case presentation: An 11-year-old boy exhibited hypotonia, poor growth, short stature, and microcephaly. The patient displayed various neurological symptoms, such as developmental delay, seizures, hydrocephalus, and brain abnormalities. He presented with strabismus, urinary problems, and facial dysmorphism. A history of stroke, obsession, insomnia, self-injurious behavior, and hearing loss was also noted. Based on the patient's clinical findings, whole exome sequencing was performed. A novel variant in the SON gene was identified. This variant was confirmed by Sanger sequencing. Notably, the parents tested normal for the variant.

Conclusion: This study presents a patient who exhibited a wide range of behavioral abnormalities, stroke, and recurrent urolithiasis - features that are rarely reported in ZTTK syndrome - and includes a review of the literature.