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. 2022 Apr 4;15(1):78.
doi: 10.1186/s12920-022-01228-6.

Neurodevelopmental disorder with microcephaly, hypotonia, and variable brain anomalies in a consanguineous Iranian family is associated with a homozygous start loss variant in the PRUNE1 gene

Mehdi Agha Gholizadeh  1   2 , Mina Mohammadi-Sarband  3 , Fatemeh Fardanesh  3 , Masoud Garshasbi  4   5
Affiliations

Neurodevelopmental disorder with microcephaly, hypotonia, and variable brain anomalies in a consanguineous Iranian family is associated with a homozygous start loss variant in the PRUNE1 gene

Mehdi Agha Gholizadeh et al. BMC Med Genomics. .

Abstract

Background: Homozygous or compound heterozygous PRUNE1 mutations cause a neurodevelopmental disorder with microcephaly, hypotonia, and variable brain malformations (NMIHBA) (OMIM #617481). The PRUNE1 gene encodes a member of the phosphoesterase (DHH) protein superfamily that is involved in the regulation of cell migration. To date, most of the described mutations in the PRUNE1 gene are clustered in DHH domain.

Methods: We subjected 4 members (two affected and two healthy) of a consanguineous Iranian family in the study. The proband underwent whole-exome sequencing and a start loss identified variant was confirmed by Sanger sequencing. Co-segregation of the detected variant with the disease in family was confirmed.

Results: By whole-exome sequencing, we identified the a start loss variant, NM_021222.3:c.3G>A; p.(Met1?), in the PRUNE1 in two patients of a consanguineous Iranian family with spastic quadriplegic cerebral palsy (CP), hypotonia, developmental regression, and cerebellar atrophy. Sanger sequencing confirmed the segregation of the variant with the disease in the family. Protein structure analysis also revealed that the variant probably leads to the deletion of DHH (Asp-His-His) domain, the active site of the protein, and loss of PRUNE1 function.

Conclusion: We identified a start loss variant, NM_021222.3:c.3G>A; p.(Met1?) in the PRUNE1 gene in two affected members as a possible cause of NMIHBA in an Iranian family. We believe that the study adds a new pathogenic variant in spectrum of mutations in the PRUNE1 gene as a cause of PRUNE1-related syndrome.

Keywords: NMIHBA; Neurodevelopmental disorder; PRUNE1; Whole-exome sequencing.

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Conflict of interest statement

The authors declare that they have no competing interests.

Figures

Fig. 1
Fig. 1
Pedigree and chromatograms in the family. a The pedigree is comprised of four generations. The black arrow shows the proband of the family. The variant, c.3G>A in PRUNE1, has been demonstrated that segregated in this family. b Sequence chromatogram showing a heterozygous and homozygous state of c.3G>A variant in PRUNE1 in the proband's parents (III:4; III:5) and the patients (III:2; IV:1), respectively. c Integrative Genomics Viewer of the genome sequencing revealed a homozygous state of c.3G>A variant in the patient (IV:1). d Schematic representation of filtering strategies exploited in this study
Fig. 2
Fig. 2
a Pathogenic variants in PRUNE1 identified in NMIHBA patients reported to date. The majority of pathogenic variants cluster in the DHH domain. b The amino acid residues of PRUNE1 are colored based on conservation scores by the ConSurf database. UCSC and Consurf database demonstrate evolutionary conservation in nucleotide and protein levels of the variant site, c.3G>A; p.(Met1?), respectively. c The three-dimensional structure of PRUNE1 is shown. The picture was delineated by using UCSF Chimera (v:1.15). Protein structure reveals the translation can be initiate at a downstream site at codon 183 would cause the deletion of the DHH domain
See this image and copyright information in PMC

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