American Journal of Medical Genetics Part A最新文献

The Homologous Recombination Factor With OB-Fold (HROB) plays a role in homologous recombination and DNA replication, where it enhances the MCM8-MCM9 helicase complex activity. Recent findings link biallelic germline HROB variants to primary gonadal insufficiency (hypergonadotropic hypogonadism), a phenotype also associated with MCM8/MCM9 deficiency. Here, we describe a family where two individuals with biallelic HROB variants presented with hypergonadotropic hypogonadism and colonic polyposis. Exome sequencing identified three unique HROB variants: a likely pathogenic nonsense variant (c.1267C>T [p.(Gln423*)]) in exon four, and two missense variants (c.1363C>G [p.(Leu455Val)] and c.1318A>G [p.(Ser440Gly)]) in exon five. RNA analysis and protein mapping indicate that the nonsense variant is likely pathogenic, whereas the missense variants remain of uncertain significance. Mutational signature analysis of polyposis tissue did not reveal signatures directly linked to HROB deficiency, yet a review of published cases and analyses of cohorts with unexplained polyposis/cancer identified additional individuals with HROB variants exhibiting hypergonadotropic hypogonadism or colonic polyposis. These findings reinforce the association between biallelic germline HROB variants and hypergonadotropic hypogonadism and suggest a potential role in colonic polyposis predisposition. We recommend incorporating HROB into diagnostic gene panels for hypergonadotropic hypogonadism, especially in cases where colonic polyposis is also present. Furthermore, we emphasize the importance of additional studies to comprehensively characterize HROB's phenotypic impact and assess its contribution to disease risk.

Genetic testing using targeted panels or comprehensive genome sequencing is the current standard for diagnosing Duchenne muscular dystrophy (DMD), identifying pathogenic variants in up to 98% of cases. We report a 5-year-old male presenting with delayed motor milestones, frequent falls, and difficulty climbing stairs due to generalized muscle weakness. Laboratory studies revealed markedly elevated CK (13,041 U/L) and chronic transaminase elevation. Clinical examination demonstrated Gower's sign, calf pseudohypertrophy, neuromuscular scoliosis, and cognitive impairment. Initial neuromuscular gene panel testing identified several variants of uncertain significance, and muscle biopsy showed markedly reduced dystrophin labeling. Follow-up short-read DMD sequencing with deletion/duplication analysis at Age 11 remained negative. Given persistently negative findings, we utilized optical genome mapping (Bionano Genomics) and long-read sequencing (Oxford Nanopore Technologies) to identify potential structural variants. Both methods independently detected a novel inversion identified to span 31 kb and encompassing exons 68-73 of the DMD gene (ChrX: 31,171,362-31,202,982), classified as pathogenic. This case highlights a clinically definitive diagnosis of DMD missed by standard genetic testing. Our findings demonstrate that Optical Genome Mapping and Long-Read Sequencing provide complementary, high-resolution tools for identifying previously unidentified structural variants and should be considered in unresolved cases prior to invasive procedures such as muscle biopsy.

The AKT2-related hypoinsulinemic hypoglycemia and overgrowth syndrome was initially described over 30 years ago as MORFAN syndrome which was an acronym for Mental retardation, pre- and post-natal Overgrowth, Remarkable Face, and Acanthosis Nigricans. Despite the limited possibility of confirming a diagnosis on the molecular level at that time, a comprehensive 30-year follow-up of a patient facilitated a detailed exploration of the syndrome's clinical trajectory. This article presents a case report spanning three decades, highlighting the significance of detailed clinical follow-up in understanding and studying this unique syndrome. Although initially associated with intellectual deficiency, the patient's intellectual abilities remain largely within the normal range. Neuropsychological examinations revealed selective neurocognitive impairment, with a predominant disruption in psychomotor speed and executive functions. Molecular genetic examination confirmed a pathogenic variant in the AKT2 gene, associated with impaired insulin metabolism and increased tumorigenesis risk. Neurooncological assessments revealed intracranial meningiomatosis, emphasizing the syndrome's potential oncological implications. Surgical interventions addressed various complications, including meningiomas and renal hamartomas. The presented case offers valuable insights into the long-term natural history of AKT2-related hypoinsulinemic hypoglycemia and overgrowth syndrome, suggesting the importance of regular oncological surveillance due to its predisposition to tumorigenesis, thereby providing clinical considerations for future cases based on long-term follow-up experience.

Transient neonatal zinc deficiency (TNZD) is a genetic condition that presents with dermatitis, alopecia, diarrhea, and growth faltering in breast milk-fed infants of females with a heterozygous pathogenic variant in SLC30A2, the primary zinc transporter in mammary glands. Despite being an easily treatable condition, effectively evaluating for TNZD can be challenging because the infant's genotype does not reliably reflect the mother's genotype. Herein, we present our approach to diagnosis in an exclusively breastfed 5-month-old infant with treatment-refractory eczematous rash, admitted for growth faltering and decreased serum zinc and alkaline phosphatase levels. The infant was diagnosed with TNZD via trio genome-based exome sequencing after a heterozygous SLC30A2 variant of uncertain significance (VUS) (c.927G>C; p.Trp309Cys) was identified in the proband's mother, which was notably absent in the proband. Breast milk zinc concentration ([Zn]) was measured in duplicate via inductively coupled mass spectrometry in 10 samples (3 from the proband's mother and 7 from unrelated controls) and measured -265, -144, and -46 μg/dL below expected [Zn] at 0, 5, and 7 months postpartum, respectively, compared to an average deviation of -29 μg/dL in controls. Zinc supplementation in the infant led to rapid clinical improvement. The absence of the maternal SLC30A2 variant in the proband underscores diagnostic challenges in evaluating for TNZD, as primary variant analysis is typically limited to the proband in trio testing. Though the prevalence of SLC30A2 disease-causing variants is unclear, carrier screening may provide a unique opportunity to proactively identify females with known pathogenic SLC30A2 variants that would impart risk to their future breastfed children and breast milk recipients.

Combined oxidative phosphorylation deficiency 4 (COXPD4) is a rare mitochondrial condition caused by biallelic deleterious variants in the nuclear-encoded gene TUFM. To date, most individuals with COXPD4 have presented with encephalopathy, hypotonia, and abnormal brain imaging. Many of the reported individuals died in infancy. We aim to expand the clinical and biochemical phenotype of COXPD4 by reporting on an adult with this condition. Our proband has a homozygous TUFM c.1025T>G, p.(Val342Gly) variant. He has sensorineural hearing loss, hyperlactatemia with mild illness, and reduced activity in mitochondrial complexes I, III, and IV on endomyocardial biopsy. He presents with hypertrophic cardiomyopathy and chronic kidney failure, which have not previously been reported in this condition. Our findings suggest not all individuals with COXPD4 present with significant neurological involvement and highlight the importance of considering COXPD4 as part of the differential diagnosis of hypertrophic cardiomyopathy.

Noonan syndrome (NS) is a genetically heterogeneous disorder characterized by a broad spectrum of clinical features resulting from dysregulation of the RAS/MAPK pathway. Although complex genotypes are increasingly recognized in NS, cases harboring two distinct pathogenic variants in different NS genes remain extremely rare. We describe the case of a 53-year-old female presenting a severe NS phenotype-including short stature, facial dysmorphism, congenital heart defect, and developmental delay-and concurrent acute myeloid leukemia (AML). Targeted NGS analysis of a RASopathy-specific gene panel identified a constitutional heterozygous PTPN11 variant (c.1472C>T, p.(Pro491Leu)) and a mosaic RIT1 variant (c.229G>C, p.(Ala77Pro), 16.45% VAF), both meeting criteria for pathogenicity. The RIT1 variant was validated via PCR-RFLP across multiple tissues, excluding leukemia-driven clonal expansion, and further quantified by high-depth amplicon-based sequencing. To our knowledge, this case represents a unique example of NS associated with pathogenic variants in two distinct RASopathy genes. Our findings underscore that comprehensive molecular characterization and multi-tissue validation are essential for accurate diagnosis, genetic counseling, and personalized management, while also revealing that combinatorial RAS/MAPK alterations may influence disease severity and clinical outcomes.

We report a 5-year-old Spanish male with a homozygous SPOUT1 variant (NM_016390.4:c.1058C>T; p.Thr353Met), identified by re-analysis of whole-genome sequencing. His phenotype includes severe developmental delay, microcephaly, epilepsy evolving to Lennox-Gastaut-like syndrome, growth impairment, dysmorphic features, and multiple congenital anomalies. Our case expands the SPOUT1-related neurodevelopmental spectrum and underscores the diagnostic value of periodic genomic data re-analysis.

Encephalocraniocutaneous lipomatosis (ECCL) is a neurocutaneous condition caused by postzygotic mosaic activating variants in genes including FGFR1, NRAS, or KRAS. It primarily affects the skin, eyes, and central nervous system. Diagnosis is typically based on characteristic clinical features and/or molecular confirmation. Here we report a unique case of ECCL in a 12-year-old female with abdominal wall lipoma, ipsilateral lower limb overgrowth, and brachydactyly, in whom somatic mosaicism for FGFR1 was identified using resected lipomatous tissue. Imaging studies confirmed additional spinal lipomas consistent with ECCL. This report expands the phenotypic spectrum of FGFR1-ECCL and underscores the importance of tissue-based somatic testing for diagnosis. Tumor risk is also discussed.

Mitochondria are essential intracellular organelles that play a critical role in cellular metabolism, including the regulation of intracellular calcium signaling. Advances in genomic sequencing have facilitated the identification of rare pathogenic mitochondrial DNA (mtDNA) genetic variants in patients with unexplained endocrine disorders. We present a case report of a woman diagnosed with the rare mtDNA variant m.10010T>C. The case report includes a detailed clinical evaluation, heteroplasmy measurements across several tissues, and a review of previously published cases of patients heteroplasmic for the m.10010T>C variant. The patient developed myopathy and exercise-induced dyspnoea at 24 years of age. Nineteen years later, progressive muscle symptoms were accompanied by elevated blood lactate and hypoparathyroidism. Muscle biopsy revealed abnormal mitochondrial morphology with cytochrome C oxidase-negative fibers and deficiencies in respiratory chain Complexes I, II, and IV. Genetic analysis identified the m.10010T>C variant with 95% heteroplasmy in the muscle biopsy, 20% in urine, 4% in buccal mucosa, and undetectable in blood (< 1%). We report the first case of a m.10010T>C carrier with hypoparathyroidism, which is a rare and unexplained finding in mitochondrial disorders that may exacerbate myopathy.