American Journal of Medical Genetics Part A最新文献

{"title":"Expanded Clinical Phenotype and the Role of Untargeted Metabolomics Analysis in Confirming the Diagnosis of Sodium-Dependent Multivitamin Transporter Deficiency.","authors":"Ameya S Walimbe, Emily Waskow, Laura Mackay, Marcus Miller, Charul Gijavanekar, Charles R Difalco, Sarah H Elsea, Fernando Scaglia","doi":"10.1002/ajmg.a.64014","DOIUrl":"https://doi.org/10.1002/ajmg.a.64014","url":null,"abstract":"<p><p>The sodium-dependent multivitamin transporter (SMVT) is a ubiquitously expressed sodium-solute symporter that transports pantothenic acid, biotin, and α-lipoic acid across the intestinal epithelia and blood-brain barrier. Severe biallelic loss-of-function variants in SLC5A6 (MIM #604024) lead to SMVT deficiency (SMVTD, MIM #618973), which classically presents with developmental delay, brain atrophy, epilepsy, sensorineural hearing loss, peripheral neuropathy, and gastrointestinal, cutaneous, and immunologic abnormalities. We describe a 25-year-old female with autism spectrum disorder (ASD), intellectual disability, agenesis of the corpus callosum (ACC), and epilepsy who presented at 15 years of age with a severe metabolic crisis characterized by hyperammonemia, lactic acidosis, and rhabdomyolysis. Trio exome sequencing (ES) identified compound heterozygous variants in SLC5A6. Plasma untargeted metabolomics analysis demonstrated reduced pantothenate and coenzyme A with elevated long-chain fatty acids, indicating impaired fatty acid oxidation, functionally validating ES results, and confirming a diagnosis of SMVTD. Targeted replacement with biotin, lipoic acid, and pantothenic acid improved her neurocognitive function and metabolic control. Our patient, the oldest reported at diagnosis, expands the phenotype of SMVTD to include rhabdomyolysis, ACC, and ASD. Our study suggests that integrating ES and untargeted metabolomics in undiagnosed patients with suspected inborn errors of metabolism may help identify this ultra-rare disorder.</p>","PeriodicalId":7507,"journal":{"name":"American Journal of Medical Genetics Part A","volume":" ","pages":"e64014"},"PeriodicalIF":1.7,"publicationDate":"2025-02-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143078380","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Evidence That Long-Term Treatment Prevents Tissue Oxidative Damage in Patients With Inherited Disorders of the Propionate Pathway.","authors":"Bianca Gomes Dos Reis, Graziela Schmitt Becker, Desiree Padilha Marchetti, Daniella de Moura Coelho, Angela Sitta, Moacir Wajner, Carmen Regla Vargas","doi":"10.1002/ajmg.a.63893","DOIUrl":"10.1002/ajmg.a.63893","url":null,"abstract":"<p><p>Propionic and methylmalonic acidemias (PAcidemia and MMAcidemia, respectively) are genetic disorders clinically characterized by metabolic decompensation associated with life-threatening encephalopathic episodes in the neonatal period. Adequate and rapid therapeutic management is essential for patients' survival and prognosis. In this study, a restricted protein diet associated with L-carnitine (LC) supplementation was shown to decrease mortality and morbidity in patients affected by these disorders probably by decreasing the accumulation of the major metabolites and therefore their toxicity. Since oxidative stress was proposed as a contributing mechanism of tissue damage in PAcidemia and MMAcidemia and LC has potent antioxidant properties, our objective in this work was to investigate the effects of a long-term therapy consisting of reduced protein intake associated with LC supplementation on oxidative damage markers in patients affected by these diseases. We measured urinary isoprostanes, di-tyrosine, and oxidized guanine species, which reflect oxidative damage to lipids, proteins, and DNA/RNA, respectively, as well as the concentrations of NO products (nitrate plus nitrite) in patients untreated or submitted to short-term or a long-term treatment. Results revealed significant increases of isoprostanes, di-tyrosine, and oxidized guanine species, as well as a moderate nonsignificant increase of NO levels in the untreated patients, relatively to controls. Furthermore, these altered markers were attenuated after short-term treatment and normalized after prolonged treatment. In conclusion, data from this work show for the first time that long-standing treatment of patients with disorders of the propionate pathway can protect against oxidative damage. However, it remains to be elucidated whether oxidative stress identified in this study directly correlates with the clinical conditions of the affected patients.</p>","PeriodicalId":7507,"journal":{"name":"American Journal of Medical Genetics Part A","volume":" ","pages":"e63893"},"PeriodicalIF":1.7,"publicationDate":"2025-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142363960","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Bullous Lung Disease in Turner Syndrome: An Underrecognized Comorbidity?","authors":"Stevin Lu, Lois J Starr, Rachel A Taylor, Anji T Yetman","doi":"10.1002/ajmg.a.63908","DOIUrl":"10.1002/ajmg.a.63908","url":null,"abstract":"<p><p>Congenital pulmonary anomalies in Turner syndrome (TS) are rarely reported. Herein, we describe a female with TS who presented with emphysema in infancy and developed pulmonary hypertension in adulthood. A 4-month-old patient presented with recurrent emesis and failure to thrive. Diagnostic testing indicated cardiomegaly and echocardiogram revealed abnormalities including left aortic arch with aberrant right subclavian artery, aortic coarctation, and left ventricular (LV) dysfunction. At 19-months, she underwent surgical intervention through a lateral thoracotomy which exposed numerous small air-filled blebs over the left lung. She had persistent LV dysfunction postoperatively. At 12-years-old, genetic testing revealed 45,X/46,Xidic(Y)(q11.22) and she subsequently received routine treatment for Turner syndrome. At 23-years-old, this patient presented to the emergency department with dyspnea, worsening cough, and edema. Echocardiogram demonstrated a reduced LVEF, aortic valve insufficiency, and pulmonary artery (PA) hypertension. CT chest showed multiple apical blebs and cardiac catheterization demonstrated pulmonary hypertension. She was treated with intravenous diuresis and cessation of Humira, which normalized LVEF and reduced PA pressure. Repeat cardiac catheterization 6 months later indicated elevated LVEDP, pulmonary vascular resistance, and mean PA pressures. Altered lymphatic drainage in utero of patients with TS may lead to emphysematous changes in the lungs. These changes may not raise concern in infancy but can possibly contribute to cardiopulmonary pathology in the future. We recommend ongoing routine care to monitor for acquired cardiopulmonary co-morbidities. Bullous lung disease may occur due to altered lymphatic drainage in patients with TS and may be a risk factor for developing or contributing to pulmonary hypertension.</p>","PeriodicalId":7507,"journal":{"name":"American Journal of Medical Genetics Part A","volume":" ","pages":"e63908"},"PeriodicalIF":1.7,"publicationDate":"2025-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142399112","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Prevalence of Individuals With Multiple Diagnosed Genetic Diseases in the Undiagnosed Diseases Network.","authors":"Alex F Gimeno, Rory J Tinker, Yutaka Furuta, John A Phillips","doi":"10.1002/ajmg.a.63888","DOIUrl":"10.1002/ajmg.a.63888","url":null,"abstract":"<p><p>Report the prevalence of multiple genetic diseases in the Undiagnosed Diseases Network (UDN) cohort in the post-exome-sequencing era. UDN subjects underwent genome sequencing before inclusion in the cohort. Records of all UDN subjects until January 2024 were analyzed. The number of diagnoses, proportion of molecular versus nonmolecular (i.e., not attributable to a discretely identifiable genetic change) diagnoses, and the inheritance patterns of the genetic diagnoses were determined. Of 2799 subjects, 766 (27.4%) had diagnoses. Of these 766, 95.4% had one diagnosis, 4.0% had two diagnoses, and 0.5% had three diagnoses. Of the diagnosed subjects, 93.4% had a genetic disease, and 6.5% had a nonmolecular disease. Of subjects with two diagnoses, both diagnoses were molecular in 90.3%, while 9.7% had one molecular and one nonmolecular diagnosis. All four subjects with three diagnoses had three molecular diagnoses. 4.2% of diagnosed subjects in the UDN had more than one molecular diagnosis, with four individuals having three concurrent Mendelian diagnoses. Additionally, three subjects had concurrent molecular and nonmolecular diagnoses. Given that numerous UDN subjects had a negative genome sequence prior to UDN enrollment, multiple molecular diagnoses may contribute to diagnostic uncertainty even with genome sequencing, as may concurrent nonmolecular disease.</p>","PeriodicalId":7507,"journal":{"name":"American Journal of Medical Genetics Part A","volume":" ","pages":"e63888"},"PeriodicalIF":1.7,"publicationDate":"2025-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142339239","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Managing CDH1 Cancer Risks in a Child: Complex Decision Making in a Family With Hereditary Diffuse Gastric Cancer.","authors":"Nihat Bugra Agaoglu, Ozden Hatirnaz Ng, Itir Ebru Zemheri, Busra Unal, Nelgin Gerenli, Ilkay Tosun, Hulya Yazıcı, Ugur Ozbek, Junne Kamihara, Huma Q Rana","doi":"10.1002/ajmg.a.63897","DOIUrl":"10.1002/ajmg.a.63897","url":null,"abstract":"<p><p>Germline pathogenic variants (PVs) in CDH1 cause hereditary diffuse gastric cancer. The management of CDH1 cases with a positive family history includes total prophylactic gastrectomy or intensive surveillance. In this study, we report a 16-year-old boy with intramucosal gastric signet ring cells in the setting of a germline CDH1 PV and a family history of early-onset gastric cancer. The approach to managing both the proband and their 9-year-old sister, who also had the CDH1 PV, presented a challenge to both clinicians and the family. Herein, we present the complexities of managing gastric cancer risk when a CDH1 PV is identified in childhood in the setting of a family history of early-onset gastric cancer.</p>","PeriodicalId":7507,"journal":{"name":"American Journal of Medical Genetics Part A","volume":" ","pages":"e63897"},"PeriodicalIF":1.7,"publicationDate":"2025-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142399113","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"KIF11 Variants Associated With Novel Renal System Involvement-Two Cases That Expand the Phenotypic Spectrum of Microcephaly With or Without Chorioretinopathy, Lymphedema, or Impaired Intellectual Development.","authors":"Tessa Gonzalez, Rebecca C Tyler, Kala F Schilter, Julie McCarrier, Michael Muriello, Donald Basel, Honey V Reddi","doi":"10.1002/ajmg.a.63903","DOIUrl":"10.1002/ajmg.a.63903","url":null,"abstract":"<p><p>Pathogenic variants in KIF11 are linked to microcephaly with or without chorioretinopathy, lymphedema, or impaired intellectual development (MCLMR). To our knowledge, renal phenotypes have not been described in the literature in association with KIF11-related disorders. This study is a case report of two probands with heterozygous pathogenic variants in KIF11 who presented with the common clinical features of MCLMR but also had additional renal involvement not previously reported as associated phenotypes of MCLMR, elucidating phenotypic expansion of this syndrome.</p>","PeriodicalId":7507,"journal":{"name":"American Journal of Medical Genetics Part A","volume":" ","pages":"e63903"},"PeriodicalIF":1.7,"publicationDate":"2025-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142455917","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Case Report of Friedreich's Ataxia and ALG1 -Related Biochemical Abnormalities in a Patient With Progressive Spastic Paraplegia.","authors":"Aisling Quinlan, Lance Rodan, Elizabeth Barkoudah, Amy Tam, Afshin Saffari, Ibrahim Shammas, Wasantha Ranatunga, Eva Morava-Kozicz, Devin Oglesbee, Gerald Berry, Darius Ebrahimi-Fakhari, Siddharth Srivastava","doi":"10.1002/ajmg.a.63890","DOIUrl":"10.1002/ajmg.a.63890","url":null,"abstract":"<p><p>Frataxin is an evolutionarily conserved mitochondrial protein responsible for iron homeostasis and metabolism. A deficiency of frataxin (encoded by FXN) leads to Friedreich's ataxia (FRDA), a progressive disorder that affects both the central and peripheral nervous systems, most commonly via a pathogenic GAA trinucleotide expansion. In contrast, pathogenic variants in ALG1 in humans cause a form of congenital disorder of glycosylation. Here, we present a 15-year-old boy with a clinical presentation that raised concern for complex hereditary spastic paraplegia (HSP), with motor features including progressive spastic paraparesis, cervical dystonia, cerebellar dysfunction, and diminished lower extremity reflexes. The proband was initially found to have a novel compound heterozygous variant in ALG1 on exome sequencing, along with N-glycan profiling revealing evidence of defective mannosylation and Western blot analysis demonstrating an 84% reduction in ALG1 expression. Although several of his clinical features could be explained by the ALG1 variant specifically or considered as part of the presentation of CDGs in general, there were additional phenotypes that suggested an alternative, or additional, genetic diagnosis. Subsequently, he was found to have biallelic pathogenic GAA repeat expansions in FXN on genome sequencing, leading to a diagnosis of FRDA. Given that FRDA explained all his clinical features, the ALG1 variant may have been a hypomorphic form and/or a biochemical phenotype. Our findings underscore the importance of considering FRDA as a differential diagnosis in cases of complex HSP and demonstrate the utility of unbiased genome sequencing approaches that include detection of trinucleotide repeat expansions for progressive motor disorders.</p>","PeriodicalId":7507,"journal":{"name":"American Journal of Medical Genetics Part A","volume":" ","pages":"e63890"},"PeriodicalIF":1.7,"publicationDate":"2025-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11698633/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142339236","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Severe Phenotype With RECQL4 Syndrome: A Report of Two Cases.","authors":"Yu Kanai, Hironori Takahashi, Fuyuki Hasegawa, Asuka Hori, Hisato Suzuki, Shoko Takahashi, Hiroko Fukushima, Hidetoshi Takada, Kenji Horie, Katsunori Ozawa, Rieko Furukawa, Kenjiro Kosaki, Kenichiro Hata","doi":"10.1002/ajmg.a.63884","DOIUrl":"10.1002/ajmg.a.63884","url":null,"abstract":"<p><p>Baller-Gerold syndrome (BGS, OMIM: 218600), RAPADILINO syndrome (OMIM 266280), and Rothmund-Thomson syndrome (RTS, OMIM 266280), which are caused in some cases by RECQL4 pathogenic variants, show autosomal recessive inheritance. Some refer to them collectively as RECQL4 syndromes. Most cases have been reported during infancy and childhood periods. However, there have been no reports of phenotypes resulting in a lethal course in the perinatal period. We identified two fetuses with biallelic RECQL4 pathogenic variants during the perinatal period. The two fetuses with RECQL4 syndrome showed structural abnormalities, including severely hypoplastic forearms and lower legs. One fetus also had severe pulmonary hypoplasia. One case resulted in neonatal death because of respiratory failure, and the other was artificially terminated during pregnancy. The RECQL4 pathogenic variants were identified by exome sequencing followed by Sanger sequencing. The biallelic RECQL4 pathogenic variants can induce a lethal skeletal disorder.</p>","PeriodicalId":7507,"journal":{"name":"American Journal of Medical Genetics Part A","volume":" ","pages":"e63884"},"PeriodicalIF":1.7,"publicationDate":"2025-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142339240","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Bi-Allelic Splicing Variant, c.153-2A > C in TOMM7 Is Associated With Leigh Syndrome.","authors":"Mayuri Yeole, Purvi Majethia, Shahyan Siddiqui, Katta Mohan Girisha, Anju Shukla, Periyasamy Radhakrishnan, Vivekananda Bhat","doi":"10.1002/ajmg.a.63892","DOIUrl":"10.1002/ajmg.a.63892","url":null,"abstract":"<p><p>Translocase of the outer mitochondrial membrane (TOMM) complex plays an important role in the transport of proteins from the cytoplasm into the mitochondria. TOMM7, one of the subunits of the TOMM complex, modulates its assembly and stability. Bi-allelic disease-causing variants in TOMM7 (MIM* 607980) have been previously reported in two unrelated families with a diverse phenotype of short stature, lipodystrophy, progeria, developmental delay, hypotonia, and skeletal dysplasia. We report a 4-month-old female child significantly affected with neonatal-onset hypotonia, lactic acidosis, optic atrophy, and neuroimaging findings suggestive of Leigh disease with a novel canonical splice variant, c.153-2A > C in TOMM7 (NM_019059.5). Further work done on cDNA of parents revealed the presence of shorter transcripts secondary to aberrant splicing.</p>","PeriodicalId":7507,"journal":{"name":"American Journal of Medical Genetics Part A","volume":" ","pages":"e63892"},"PeriodicalIF":1.7,"publicationDate":"2025-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142339235","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Promoter Deletion Leading to Allele Specific Expression in a Genetically Unsolved Case of Primary Ciliary Dyskinesia.","authors":"M Makenzie Beaman, Weining Yin, Amanda J Smith, Patrick R Sears, Margaret W Leigh, Thomas W Ferkol, Brendan Kearney, Kenneth N Olivier, Adam J Kimple, Shannon Clarke, Erin Huggins, Erica Nading, Seung-Hye Jung, Apoorva K Iyengar, Xue Zou, Hong Dang, Alejandro Barrera, William H Majoros, Catherine W Rehder, Timothy E Reddy, Lawrence E Ostrowski, Andrew S Allen, Michael R Knowles, Maimoona A Zariwala, Gregory E Crawford","doi":"10.1002/ajmg.a.63880","DOIUrl":"10.1002/ajmg.a.63880","url":null,"abstract":"<p><p>Variation in the non-coding genome represents an understudied mechanism of disease and it remains challenging to predict if single nucleotide variants, small insertions and deletions, or structural variants in non-coding genomic regions will be detrimental. Our approach using complementary RNA-seq and targeted long-read DNA sequencing can prioritize identification of non-coding variants that lead to disease via alteration of gene splicing or expression. We have identified a patient with primary ciliary dyskinesia with a pathogenic coding variant on one allele of the SPAG1 gene, while the second allele appears normal by whole exome sequencing despite an autosomal recessive inheritance pattern. RNA sequencing revealed reduced SPAG1 transcript levels and exclusive allele specific expression of the known pathogenic allele, suggesting the presence of a non-coding variant on the second allele that impacts transcription. Targeted long-read DNA sequencing identified a heterozygous 3 kilobase deletion of the 5' untranslated region of SPAG1, overlapping the promoter and first non-coding exon. This non-coding deletion was missed by whole exome sequencing and gene-specific deletion/duplication analysis, highlighting the importance of investigating the non-coding genome in patients with \"missing\" disease-causing variation. This paradigm demonstrates the utility of both RNA and long-read DNA sequencing in identifying pathogenic non-coding variants in patients with unexplained genetic disease.</p>","PeriodicalId":7507,"journal":{"name":"American Journal of Medical Genetics Part A","volume":" ","pages":"e63880"},"PeriodicalIF":1.7,"publicationDate":"2025-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11698635/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142370743","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}