Identification of a DAGLB Mutation in a Non‐Chinese Patient with Parkinson's Disease

Liu and colleagues1 recently reported that biallelic mutations in DAGLB are responsible for autosomal recessive early-onset Parkinson's disease (AR-EO-PD). They first identified a homozygous DAGLB splice-site mutation in a consanguineous family with two affected siblings by combining homozygosity mapping and whole-exome sequencing. Through exome data mining in a large cohort of 1741 unrelated cases with PD, they identified three additional mutated index cases. All six patients were of Chinese origin and presented typical EO-PD (≤40 years) with a good response to levodopa. No additional cases outside of China have been reported so far. To assess the causal role of pathogenic variants in DAGLB in our French cohort, we used data mining in the exomes of 55 families with AR-PD (n = 88 cases) and 629 isolated EO-PD cases (Appendix S1). We identified a homozygous p.Pro357Leu missense variant in a single consanguineous PD case (Fig. 1A). This mutation, predicted to be deleterious by 13 of 18 prediction software tested (Supporting Information Table S1 in Appendix S1), affects a conserved amino acid localized in the catalytic domain of the protein, near the pathological p.Asp363Gly mutation described in a previous article1 (Fig. 1B). It is predicted to destabilize the protein structure according to Dynamut22 (Fig. 1C,D). All rare variants in the homozygous state identified in whole-exome sequencing analysis of this patient are available in Supporting Information Table S2 in Appendix S1. The patient of Algerian origin was born to healthy first-cousin parents and reported no family history of PD. His family and social circumstances led him to stop his schooling at the age of 15 years. He presented at 30 years with bradykinesia and later developed postural instability and an akinetic-rigid form of the disease, predominant on the right side, with a Unified Parkinson's Disease Rating Scale Part III (UPDRS III) motor score of 25 and a Hoehn & Yahr score of 3 with off stage and 2 under medication. After 13 years of disease evolution, his akinetic-rigid syndrome worsened with the presence of dysarthria, a UPDRS III score of 78 with off stage and of 45 on medication, and a Hoehn & Yahr stage of 4 with the off stage, which improved to 3 on medication. The patient did not show any frank cognitive impairment or hallucinations. At the last examination, he developed nonmotor signs and symptoms, such as depression, constipation, urinary disturbances, and sleep disturbances. Levodopa treatment led to significant improvement in clinical signs. The patient subsequently developed end-of-dose dyskinesias, motor fluctuations, and dystonia in the off medication state. Brain magnetic resonance imaging results were normal (see Supporting Information Table S3 in Appendix S1). Thus, we identified a patient carrying the DAGLB p.Pro357Leu mutation localized near the previously published p.Asp363Gly1 variant, reinforcing the fact that DAGLB is involved in EO-AR-PD. As the most frequent genes involved in AR-PD (PRKN,3 PINK14), the DAGLB-associated disease presents and evolves like typical PD. Because we screened a population of PD cases with either AR inheritance or EO-PD (<50 years) and found a single patient among 683 index cases, we conclude that DAGLB is a very rare cause of AR-EO-PD. However, we demonstrate that mutations in DAGLB are not limited to the Chinese PD population but can also account for PD in North Africa. We thank the patients and their families. We thank the DNA and Cell Bank of the ICM for sample preparation. Part of this work was carried out in the iGenSeq and DAC core facilities of the ICM. We thank Dr. Poornima Menon for proofreading the text. C.T.: 1A, 1B, 1C, 3A M.S.B.: 3B, 4 S.L.: 1A, 1B, 3B A.B.: 1A, 1B, 3B, 4 All authors have read and agreed to the published version of the manuscript. Informed consent was obtained from all participants, and genetic studies were approved by local ethics committees (N° 44,814; INSERM, CCPPRB du Groupe Hospitalier Pitié-Salpêtrière, Paris, France). We confirm that we have read the Journal's position on issues involved in ethical publication and affirm that this work is consistent with those guidelines. Christelle Tesson was employed by Paris Brain Institute (ICM) during this work. Suzanne Lesage has received grants from Fondation de la Recherche Médicale (FRM; MND202004011718). Alexis Brice has received grants from Fondation Roger de Spoelberch and Greater Paris University Hospitals (APHP). Data available on request from the authors. Appendix S1. Supporting Information. Please note: The publisher is not responsible for the content or functionality of any supporting information supplied by the authors. Any queries (other than missing content) should be directed to the corresponding author for the article.