TY  - JOUR
A1  - Rapp, Christina K.
A1  - Van Dijck, Ine
A1  - Laugwitz, Lucia
A1  - Boon, Mieke
A1  - Briassoulis, George
A1  - Ilia, Stavroula
A1  - Kammer, Birgit
A1  - Reu, Simone
A1  - Hornung, Stefanie
A1  - Buchert, Rebecca
A1  - Sofan, Linda
A1  - Froukh, Tawfiq
A1  - Witters, Peter
A1  - Rymen, Daisy
A1  - Haack, Tobias B.
A1  - Proesmans, Marijke
A1  - Griese, Matthias
T1  - Expanding the phenotypic spectrum of FINCA (fibrosis, neurodegeneration, and cerebral angiomatosis) syndrome beyond infancy
JF  - Clinical Genetics
N2  - Fibrosis, neurodegeneration, and cerebral angiomatosis (FINCA, MIM#618278) is a rare clinical condition caused by bi‐allelic variants in NHL repeat containing protein 2 (NHLRC2, MIM*618277). Pulmonary disease may be the presenting sign and the few patients reported so far, all deceased in early infancy. Exome sequencing was performed on patients with childhood interstitial lung disease (chILD) and additional neurological features. The chILD‐EU register database and an in‐house database were searched for patients with NHLRC2 variants and clinical features overlapping FINCA syndrome. Six patients from three families were identified with bi‐allelic variants in NHLRC2. Two of these children died before the age of two while four others survived until childhood. Interstitial lung disease was pronounced in almost all patients during infancy and stabilized over the course of the disease with neurodevelopmental delay (NDD) evolving as the key clinical finding. We expand the phenotype of FINCA syndrome to a multisystem disorder with variable severity. FINCA syndrome should also be considered in patients beyond infancy with NDD and a history of distinct interstitial lung disease. Managing patients in registers for rare diseases helps identifying new diagnostic entities and advancing care for these patients.
KW  - cerebropulmonary disease
KW  - childhood interstitial lung disease
KW  - cholesterol pneumonia
KW  - FINCA
KW  - lung fibrosis
KW  - lipoid pneumonitis
KW  - multi‐organ disease
KW  - NHLRC2
Y1  - 2021
U6  - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-262732
VL  - 100
IS  - 4
SP  - 453
EP  - 461
ER  - 
TY  - JOUR
A1  - Schuch, Luise A.
A1  - Forstner, Maria
A1  - Rapp, Christina K.
A1  - Li, Yang
A1  - Smith, Desiree E. C.
A1  - Mendes, Marisa I.
A1  - Delhommel, Florent
A1  - Sattler, Michael
A1  - Emiralioğlu, Nagehan
A1  - Taskiran, Ekim Z.
A1  - Orhan, Diclehan
A1  - Kiper, Nural
A1  - Rohlfs, Meino
A1  - Jeske, Tim
A1  - Hastreiter, Maximilian
A1  - Gerstlauer, Michael
A1  - Torrent‐Vernetta, Alba
A1  - Moreno‐Galdó, Antonio
A1  - Kammer, Birgit
A1  - Brasch, Frank
A1  - Reu‐Hofer, Simone
A1  - Griese, Matthias
T1  - FARS1‐related disorders caused by bi‐allelic mutations in cytosolic phenylalanyl‐tRNA synthetase genes: Look beyond the lungs!
JF  - Clinical Genetics
N2  - Aminoacyl‐tRNA synthetases (ARSs) catalyze the first step of protein biosynthesis (canonical function) and have additional (non‐canonical) functions outside of translation. Bi‐allelic pathogenic variants in genes encoding ARSs are associated with various recessive mitochondrial and multisystem disorders. We describe here a multisystem clinical phenotype based on bi‐allelic mutations in the two genes (FARSA, FARSB) encoding distinct subunits for tetrameric cytosolic phenylalanyl‐tRNA synthetase (FARS1). Interstitial lung disease with cholesterol pneumonitis on histology emerged as an early characteristic feature and significantly determined disease burden. Additional clinical characteristics of the patients included neurological findings, liver dysfunction, and connective tissue, muscular and vascular abnormalities. Structural modeling of newly identified missense mutations in the alpha subunit of FARS1, FARSA, showed exclusive mapping to the enzyme's conserved catalytic domain. Patient‐derived mutant cells displayed compromised aminoacylation activity in two cases, while remaining unaffected in another. Collectively, these findings expand current knowledge about the human ARS disease spectrum and support a loss of canonical and non‐canonical function in FARS1‐associated recessive disease.
KW  - aminoacyl‐tRNA synthetases
KW  - cholesterol pneumonitis
KW  - FARS1
KW  - children´s interstitial lung disease (chILD) lipoid pneumonia
Y1  - 2021
U6  - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-238827
VL  - 99
IS  - 6
SP  - 789
EP  - 801
ER  -