{"database":"biostudies-literature","file_versions":[],"scores":null,"additional":{"submitter":["McNamee L"],"funding":["NCATS NIH HHS","NHGRI NIH HHS","Common Fund","National Center for Advancing Translational Science","NINDS NIH HHS","NIH Common Fund"],"pagination":["e63798"],"full_dataset_link":["https://www.ebi.ac.uk/biostudies/studies/S-EPMC11934095"],"repository":["biostudies-literature"],"omics_type":["Unknown"],"volume":["194(11)"],"pubmed_abstract":["Although next-generation sequencing has enabled diagnoses for many patients with Mendelian disorders, the majority remain undiagnosed. Here, we present a sibling pair who were clinically diagnosed with Escobar syndrome, however targeted gene testing was negative. Exome sequencing (ES), and later genome sequencing (GS), revealed compound heterozygous TTN variants in both siblings, a maternally inherited frameshift variant [(NM_133378.4):c.36812del; p.(Asp12271Valfs*10)], and a paternally inherited missense variant [(NM_133378.4):c.12322G > A; p.(Asp4108Asn)]. This result was considered nondiagnostic due to poor clinical fit and limited pathogenicity evidence for the missense variant of uncertain significance (VUS). Following initial nondiagnostic RNA sequencing (RNAseq) on muscle and furthe"],"journal":["American journal of medical genetics. Part A"],"pubmed_title":["Reanalysis of RNA sequencing data ends diagnostic odyssey and expands the phenotypic spectrum of congenital titinopathy."],"pmcid":["PMC11934095"],"funding_grant_id":["U01 HG007703","U01 NS134350","UL1TR001881","UL1 TR001881","U01HG007703","U01 HG007672","U01HG007672","U01 NS134356","U01NS134356"],"pubmed_authors":["Dasari S","Douglas J","Cole FS","Undiagnosed Diseases Network","Emrick LT","Skelton T","Wener M","Callaway K","Novacic D","Malicdan MCV","Rajagopalan R","Taylor H","Worley K","Sutton S","Cuddapah V","Jobanputra V","Butte MJ","Walker M","Stoler JM","Ezell K","Jean-Marie O","Karasozen Y","Leppig KA","Bonner D","Gropman A","Smith EC","Seto E","Coakley TR","Pallais JC","Fieg EL","Bellen HJ","Acosta MT","Hurst A","Posey JE","Lanza IR","Rebelo A","Silverman EK","Sirugo G","Miller D","Jarvik GP","Vogel TP","Adams DR","Krakow D","Byers P","Martin MG","Shelkowitz E","Bale J","Fisher PG","Fogel BL","Maghiro A","Mahoney R","Lanpher BC","Scott DA","Smith CA","McCray AT","Phillips JA","Whitlock J","Petcharet L","Sweetser DA","Alvey J","Tran AA","Macnamara EF","Cobban LA","Raper A","Davis J","Korf B","Buckley AF","Tarakad A","Marth G","Wang LK","Cogan JD","Allenspach E","Mulvihill L","Bivona S","Tabor HK","Wenger T","Gonzalez JM","Pusey Swerdzewski BN","Bejerano G","Craigen WJ","Might M","Wangler MF","Pak S","Zuchner S","Bayrak-Toydemir P","Hisama FM","Martin BA","Hayes N","Longo N","Ketkar S","Rosenfeld JA","Mao R","Skraban C","Liu P","Sullivan K","Wambach J","Alvarez RL","Lalani SR","McNamee L","Dorrani N","Parker NH","Blue E","Orengo JP","Thorson W","Wheeler MT","Hing A","Horike-Pyne M","Martinez-Agosto JA","Bennett J","Carvalho G","Kilich G","Bamshad M","Zhang Z","Tekin M","Eng CM","D'Souza P","Hom J","Kravets E","Peart L","Hanchard N","Nelson SF","Halley MC","Smith KS","Sheppeard S","Sybert V","Delgado M","Latchman K","Introne W","Bohnsack J","Nitsuh D","Tifft CJ","Baldridge D","Lewis RA","Darr K","Holm IA","Solomon B","Solnica-Krezel L","Clark GD","Rodan LH","Afzali B","Corona RI","Byrd WE","Kohane IS","Beck A","Moretti P","Potocki L","Crouse AB","Glass I","Mikati M","Wegner D","Rives L","Coggins M","Andrews A","Kiley D","Kohler JN","Lee H","Shashi V","Behrens E","Tan ALM","Botto L","Ashley EA","Bacino CA","Chanprasert S","Barbouth D","Lark RK","Briere LC","Quinlan A","Ruzhnikov M","Wood H","Beggs AH","Marwaha S","Nakano-Okuno M","Huang Y","Hamid R","Fu J","Mitchell B","Reuter CM","Dai H","Spillmann RC","Goddard PC","Sisco K","Glanton E","Vanderver A","Balasubramanyam A","Burrage LC","Morimoto M","Shin J","Schoch K","Marom R","Ungar RA","Toro C","Pace L","Lee BH","Cassini T","Chao HT","Huang A","Oglesbee D","Velinder M","McConkie-Rosell A","Stergachis A","Maduro VV","Ganetzky R","Yamamoto S","Viskochil D","Carey J","Sampson JB","Bademci G","High F","Bernstein JA","Berry GT","Tan Q","Rader DJ","Bican A","Burke EA","Rodriguez M","Kobren SN","LeBlanc K","Lam C","Rossignol F","Walley NM","Pinto E Vairo F","Robertson AK","Hassey K","Ward PA","Earl D","MacRae CA","Hubshman MW","Rosenthal E","Chinn I","Klee E","Doherty D","Mirzaa G","Corner B","Allworth A","Maas RL","Gahl WA","Loscalzo J","Mulvihill JJ","Schedl T","Jayadev S","Rao DA","Schimmenti L","Dipple K","Kanca O","Al-Beshri A","Neumann S","Wolfe LA","Korrick S","Raskind W","Dell'Angelica EC","Borja N","Westerfield M","Douine ED","Sabaii M","Wahl CE"],"additional_accession":[]},"is_claimable":false,"name":"Reanalysis of RNA sequencing data ends diagnostic odyssey and expands the phenotypic spectrum of congenital titinopathy.","description":"Although next-generation sequencing has enabled diagnoses for many patients with Mendelian disorders, the majority remain undiagnosed. Here, we present a sibling pair who were clinically diagnosed with Escobar syndrome, however targeted gene testing was negative. Exome sequencing (ES), and later genome sequencing (GS), revealed compound heterozygous TTN variants in both siblings, a maternally inherited frameshift variant [(NM_133378.4):c.36812del; p.(Asp12271Valfs*10)], and a paternally inherited missense variant [(NM_133378.4):c.12322G > A; p.(Asp4108Asn)]. This result was considered nondiagnostic due to poor clinical fit and limited pathogenicity evidence for the missense variant of uncertain significance (VUS). Following initial nondiagnostic RNA sequencing (RNAseq) on muscle and furthe","dates":{"release":"2024-01-01T00:00:00Z","publication":"2024 Nov","modification":"2026-06-02T21:12:46.601Z","creation":"2025-07-02T03:04:41.924Z"},"accession":"S-EPMC11934095","cross_references":{"pubmed":["38924341"],"doi":["10.1002/ajmg.a.63798"]}}