Case Reports in Genetics最新文献

Background: Monocarboxylate transporter 8 (MCT8) deficiency, also known as Allan-Herndon-Dudley syndrome, is a rare X-linked genetic disorder resulting from pathogenic mutations in the SLC16A2 gene. MCT8 deficiency impacts the transport of thyroid hormone (TH) throughout the body. Symptoms are highly heterogeneous and often include severe neurodevelopmental delay, hypotonia in the limbs and trunk, and low body weight.

Case presentation: This case report describes the diagnostic journey of two brothers born 1 year and 8 months apart to nonconsanguineous parents. Both exhibited severely limited motor development, quadriparesis, and an inability to sit independently or hold their head up. Despite their significant clinical presentations, the diagnoses were delayed: 12 years and 8 months for Case 1 and 8 years and 3 months for Case 2. Genetic testing revealed that both patients carry the same novel SLC16A2 mutation, 960_995del (p.Tyr321_Ala332del). Although they displayed key clinical features of MCT8 deficiency, the TH profile of Case 1 was inconclusive, lacking the characteristic sustained elevation of triiodothyronine (T3) typically associated with MCT8 deficiency.

Conclusions: Findings from this case report highlight the need for greater awareness of this disorder and underscore the clinical heterogeneity of MCT8 deficiency.

Diaphragmatic rupture is an uncommonly seen complication of classical Ehlers-Danlos syndrome (cEDS). There have been no documented cases of diaphragmatic hernia in newborns having cEDS. This case study discusses a male infant delivered through spontaneous vertex delivery to a mother with cEDS. No evidence of a diaphragmatic hernia was found 6 days before delivery when an ultrasound scan to monitor a ventricular septal defect was carried out. Postnatally, the infant displayed signs of severe respiratory distress. A chest radiograph revealed a diaphragmatic hernia. The surgical team found and corrected a small posterolateral diaphragmatic defect on the third day of life. This resulted in a good recovery following management of a complication of chylothorax. The mother was known to have cEDS and bidirectional sequencing of the patient's lymphocyte DNA detected the heterozygous pathogenic familial variant COL1A1 c.934C > T;p.(Arg312Cys). This variant has been previously reported in cases of cEDS. Other COL1A1 variants are known to be associated with arthrochalasia-type EDS and osteogenesis imperfecta, but no COL1A1 variants have been associated previously with congenital diaphragmatic hernia or diaphragmatic rupture. The familial variant impacts the highly conserved arginine residue in the Gly-X-Y triplet motif of the Type-I collagen protein. It has been reported in various families as a rare cause of autosomal-dominant cEDS. This case report details the patient's journey, including images of radiographs, highlighting a rare but important complication of spontaneous vertex delivery for individuals with cEDS. We also include a literature review on diaphragmatic hernia and rupture in classical EDS.

Primary ciliary dyskinesia (PCD) is a rare, inherited disease resulting from abnormal structure and/or function of cilia. To date, pathogenic variants in over 50 genes have been reported as causes of PCD. One of the genes, HYDIN, presents a diagnostic challenge due to the existence of HYDIN2, a highly homologous pseudogene that significantly complicates accurate molecular diagnosis. Here, we present a 43-year-old female with a clinical diagnosis of PCD seeking molecular diagnosis underlying her disease. Short-read genome sequencing detected two potentially pathogenic HYDIN variants (c.5416C > T and c.3786-1G > T), but clinical validation was hindered due to the pseudogene overlap. Using clinical long-read genome sequencing (lrGS), we confirmed the presence of both HYDIN pathogenic variants and a trans configuration, establishing the molecular diagnosis for this patient. This case highlights the promise of lrGS in diagnosing HYDIN-related PCD and demonstrates that offering lrGS to PCD patients, especially those with suspected HYDIN variants, could enhance diagnostics, disease management, and genetic counseling.

Parkinson's disease (PD) is a neurodegenerative condition characterized by progressive loss of dopaminergic neurons and by heterogeneous etiologies and clinical manifestations. Juvenile-onset forms are rare and can be caused by biallelic mutations in several genes. Kufor-Rakeb syndrome (KRS) is an autosomal-recessive form of early-onset parkinsonism caused by pathogenic variants in the ATP13A2 (PARK9) gene. This P5B-ATPase dysfunction impairs lysosomal processing, leading to the accumulation of α-synuclein. Here, we present the first documented Guatemalan case of KRS, a young woman with progressive motor and cognitive decline. Genetic testing identified a homozygous pathogenic variant in ATP13A2. This report underscores the importance of recognizing KRS in diverse populations and of using gene-based testing to guide diagnosis, counseling, and multidisciplinary supportive care.

Juvenile polyposis syndrome (JPS) (MIM: 174900) is a rare genetic disorder characterized by multiple benign, hamartomatous polyps, and an increased risk for colorectal and gastric cancer. It is caused by pathogenic variants in SMAD4 and BMPR1A. We present the findings of a mosaic BMPR1A pathogenic variant in a 57-year-old patient with newly diagnosed colon cancer and a history of polyps, which were later discovered to be JPS polyps. The variant was first identified in a blood sample at approximately 15% allele frequency. Subsequent genetic testing performed on gDNA from cultured fibroblasts found this variant to be present at very low levels (< 10%). The finding of this BMPR1A variant in two sample types, as well as the history of JPS polyps, supports a diagnosis of JPS due to a mosaic BMPR1A pathogenic variant. This diagnosis affects cancer screening recommendations for our patient and his relatives. Our case highlights the need for recognition and workup of potentially mosaic cases and for universal germline genetic testing for patients with colorectal cancer.

The SRD5A2 gene encodes the steroid 5α-reductase-2 isozyme, which converts testosterone to dihydrotestosterone and plays a key role in sexual development and androgen physiology. Deficiency of this enzyme leads to an autosomal recessive sex-linked disorder associated with ambiguous genitalia and hypovirilization/complete feminization of external genitalia in individuals with a 46,XY karyotype. The present study emphasizes the indispensable role of molecular genetic testing in siblings (Probands 1 and 2) presented with disorders of sexual development (DSD). The biochemical, cytogenetics, and molecular testing, encompassing hormonal testing, chromosomal analysis, fluorescence in situ hybridization (FISH), and whole exome sequencing (WES), were carried out at our National Reference Laboratory. In addition, Sanger sequencing confirmed the identified variant, and bioinformatics tools were used to assess its impact on protein structure and stability, thereby assessing its pathogenic potential. The biochemical profile revealed highly elevated testosterone/dihydrotestosterone in Probands 1 and 2 as 45.4 and 43.2, respectively (biological reference range < 10). The cytogenetic analysis confirmed a 46,XY karyotype, and FISH validated the presence of the SRY gene. WES identified a pathogenic homozygous variant, c.737G > A(p.Arg246Gln) in the SRD5A2 gene. Protein structure predictions and stability analyses indicated the variant's damaging effects. This study supports diagnosis through comprehensive molecular testing and highlights the significance of genetic insights in managing 46,XY DSD. This case highlights phenotypic variability in siblings with the same homozygous SRD5A2 variant from a nonconsanguineous Indian family, underscoring the need for early genetic workup and multidisciplinary evaluation in 46,XY DSD.

Buratti-Harel syndrome (BURHAS) is a rare genetic condition caused by heterozygous pathogenic variants of the SIAH1 gene, with only five unrelated cases included in a single report in 2019. BURHAS is characterized mainly by neurodevelopmental delay, infantile hypotonia, and dysmorphic features. We report the case of a 9-year-old Chilean female that matches this phenotype, with a heterozygous, de novo frameshift variant of the SIAH1 gene.

Biallelic pathogenic variants in RAPSN cause a form of congenital myasthenic syndrome (CMS), which is typically characterized by fatiguable muscle weakness, hypotonia, and feeding difficulties that present in the neonatal period or early childhood. RAPSN-associated CMS can be treated with acetylcholinesterase inhibitors. Here, we present a 4-year-old male with a history of neonatal respiratory distress, hypotonia, and muscle weakness exacerbated by illness who underwent trio genome sequencing and was found to have biallelic single nucleotide variants at the same position in RAPSN, encoding NM_005055.5:c.264C > A p.(N88K) and NM_005055.5:c.264C > G p.(N88K). The paternally inherited c.264C > G variant has not been previously reported. Interestingly, only the maternally inherited c.264C > A variant was reported on the patient's prior clinical exome sequencing, which delayed diagnosis and initiation of treatment for this patient. This case highlights the complexity of identifying multiallelic variants during exome and genome sequencing analysis. Additionally, this case is the first report of facial malformations in a patient with RAPSN-associated CMS due to variants outside of the promoter region. Trial Registration: ClinicalTrials.gov identifier: NCT02450851.

Telomere Biology Disorders (TBD) are a group of heritable disorders characterized by short telomeres. We report two patients that presented with bone marrow failure (BMF), who were identified to have low telomere length (TL) and variants of uncertain significance (VUS) in two different telomere genes inherited from their parents. At age 6, Patient 1 had stage 4 neuroblastoma. He was treated with chemotherapy, surgery, immunotherapy, and autologous stem cell rescue. At age 10, he developed pancytopenia. Bone marrow biopsy revealed hypocellular marrow and der (1; 7), associated with myelodysplastic syndrome. Germline genetic evaluation showed a pathogenic variant in DNAJC21 (from father) and VUS in NAF1 (c.1375C > T) (from father) and RTEL1 (c.533T > C) (from mother). The patient was found to have very low TL (VLTL) (< 1st percentile) in 4/6 white blood cell subsets. The patient's mother was found to have borderline low TL (VLTL) ( 1 and < 10th percentiles) in 4/6 subsets and VLTL in 1/6 subsets. Father had VLTL in 1/6 but normal TL in other subsets. Neither parent reported any symptoms of TBD. Patient 2 presented with a depressed skull fracture at age 15. He was found incidentally to have pancytopenia. Bone marrow biopsy showed hypocellular marrow and no cytogenetic abnormalities. The patient had VLTL in all 6/6 subsets. Genetic evaluation showed VUSs in TERT (c.3158-80G > A) (from mother), TINF2 (c.814T > C) (from mother) and SRP72 (c.1928C > T) (from father). Mother was also found to have VLTL in all 6 subsets but has reported good health except for premature graying of hair. These two patients presented with BMF, identified to have VUSs in more than one TBD-associated gene with functional evidence of shortened telomeres, highlighting the potential for a digenic mode of inheritance. Synergy between two VUSs could contribute to a penetrant phenotype and resulting in earlier or more severe onset of disease.

We report a 71-year-old female patient with a history of intellectual disabilities, dysmorphic features, schizoaffective disorder, bipolar type, and psychosis. Exome sequencing revealed a novel, heterozygous, predicted loss-of-function variant in the BICRA gene (NM_015711.3: c.1910del, p.[Leu637ArgfsTer87]). Heterozygous rare variants in BICRA have been associated with Coffin-Siris Syndrome 12 (CSS-12; OMIM #619325). This is the oldest patient to date with a pathogenic variant in BICRA. This case report expands the clinical phenotype associated with BICRA variants and sheds light on the long-term prognosis.