Case Reports in Genetics最新文献

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.

[This corrects the article DOI: 10.1155/2024/6009569.].

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.

Baker-Gordon syndrome (BAGOS) is an autosomal dominant neurodevelopmental disorder caused by de novo heterozygous missense mutations in SYT1. The precise pathogenic mechanism of BAGOS is still unclear, with preliminary data favoring a dominant-negative effect, although a previous case presenting a reciprocal translocation disrupting SYT1 supports haploinsufficiency as a possible mechanism. We report a child with a syndromic neurodevelopmental disorder compatible with BAGOS and carrying a t(5; 12)(q31; q21) by G-banded karyotype. Optical genome mapping (OGM) is based on ultrahigh molecular weight DNA molecules allowing the combined analyses of numerical and structural chromosome variants. The rearrangement was investigated using OGM, which revealed an additional structural variant, a paracentric inversion in the segment of Chromosome 12 translocated to der(5). The breakpoint of the paracentric inversion is mapped to Intron 9 of the SYT1 gene, interrupting the C2B domain. This is the second BAGOS case reported in the literature caused by SYT1 disruption, supporting that reduced amounts of functional SYT1, either by haploinsufficiency or dominant-negative effect, is responsible for SYT1-associated neurodevelopmental syndrome.

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.