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Mild MDPL in a patient with a novel de novo missense variant in the Cys-B region of POLD1


DNA polymerase δ is one of the three main enzymes responsible for DNA replication. POLD1 heterozygous missense variants in the exonuclease domain result in a cancer predisposition phenotype. In contrast, heterozygous variants in POLD1 polymerase domain have more recently been shown to be the underlying basis of the distinct autosomal dominant multisystem lipodystrophy disorder, MDPL (mandibular hypoplasia, deafness, progeroid features, and lipodystrophy syndrome OMIM # 615381), most commonly a recurrent in-frame deletion of serine at position 604, accounting for 18 of the 21 reported cases of this condition. One patient with an unusually severe phenotype has been reported, caused by a de novo c. 3209 T > A, (p.(Ile1070Asn)) variant in the highly conserved CysB motif in the C-terminal of the POLD1 protein. This region has recently been shown to bind an iron-sulphur cluster of the 4Fe-4S type. This report concerns a novel de novo missense variant in the CysB region, c.3219 G > C, (p.(Ser1073Arg)) in a male child with a milder phenotype. Using in silico analysis in the context of the recently published structure of human Polymerase δ holoenzyme, we compared these and other variants which lie in close proximity but result in differing degrees of severity and varying features. We hypothesise that the c.3219 G > C, (p.(Ser1073Arg)) substitution likely causes reduced binding of the iron-sulphur cluster without significant disruption of protein structure, while the previously reported c.3209 T > A (p.(Ile1070Asn)) variant likely has a more profound impact on structure and folding in the region. Our analysis supports a central role for the CysB region in regulating POLD1 activity in health and disease.

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Fig. 1: Architecture of human DNA polymerase δ catalytic subunit and alignment of the CysB motif in POLD1 orthologues.
Fig. 2: Facial features of index case, age 5 years.
Fig. 3: Structure of POLD1 and CysB variants.
Fig. 4: Physicochemical properties of the CysA and CysB regions of POLD1.

Data availability

The variant identified in this project has been submitted to a publicly accessible genetic variant database, ClinVar. The ClinVar accession number is SUB9578857.


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The authors of this paper wish to acknowledge the patient and family for their participation in this study. The authors would also like to thank Andrew Hattersley for his critical review of the paper. The authors of this paper wish to acknowledge the Fondation Bettencourt-Schueller, MSD-France and the patient organization “S’entendre” for their financial supports.

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Correspondence to Sandrine Marlin.

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Chopra, M., Caswell, R., Barcia, G. et al. Mild MDPL in a patient with a novel de novo missense variant in the Cys-B region of POLD1. Eur J Hum Genet 30, 960–966 (2022).

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