Novel Frameshift Variant in The PCNT Gene Associated With Microcephalic Osteodysplastic Primordial Dwarfsm (MOPD) Type II And Small Kidneys Ⅱ
Nov 14, 2023
Discussion and conclusion
Herein we described the first genetically confrmed case of Microcephalic Osteodysplastic Primordial Dwarfsm (MOPD) Type II in a patient of Sri Lankan origin. Based on the genetic diagnosis the parents were counselled and multidisciplinary shared care was arranged locally
Growth monitoring was carried out with specific growth curves designed for this condition [10]. Thus, growth parameters of the proband were plotted between median and SD in MOPD Type II specific growth curves. A study conducted on 47 individuals with this condition revealed 64% of the study population was diagnosed with a vascular condition such as moyamoya and intracranial aneurysms or both. Additionally, vascular complications involving the renal arteries, coronaries, and external carotids were also reported in this group [2]. The proband had normal findings in the baseline ultrasound KUB and MRI brain. However, structural heart defects were reported which is a rare phenotype [11].
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Due to the high risk of neurovascular manifestations in later life, routine surveillance was arranged as recommended in the literature. Proband will be followed up with multidisciplinary inputs by a cardiologist and neurologist. Furthermore, we observed bilaterally small kidneys in the proband, which was not described with MOPD Type II before. Yearly skeletal surveillance to identify hip pathologies such as hip dislocations and sco-losis is also essential, a narrow dysplastic hip with a fat acetabulum is a cardinal feature [12]. Oro dental findings such as microdontia, malformed teeth, short roots especially of the molars, tooth agenesis, and enamel hypoplasia are commonplace. Hence proper dental care and regular follow-up with a dentist are essential. Teir also prone to endocrine abnormalities, mainly insulin resistance which should be anticipated after 5 years of age. Growth hormone therapy is not usually recommended considering the risk of scoliosis and the lack of evidence in the outcome.
MOPD Type II affects multiple organ systems this could reflect the spindle dysfunction caused by PCNT variants. Thus, the loss of function of pericentrin is implicated in the mislocalization of cellular proteins due to mitotic spindle defects causing missegregation of chromosomes, mitotic failure with eventual cell arrest, and cell death [13]. Pericentrin binds calmodulin expressed in the centrosomes, it contains a series of coiled-coil domains that interact with the microtubule nucleation component gamma-tubulin which is essential throughout the cell cycle. As confrmed by protein modeling approaches defects in the protein–protein interaction domains of PCNT could have contributed to the phenotype of MOPD Type II in our patient. According to the literature, there was a high incidence of cerebrovascular malformations when the last exons from 30 to 43 were involved [12]. The two variants identified in the proband c.9535dup (p.Val3179fs) reside in exon 43 and c.5059_5060delAA (p. Asn1687fs) resides in exon 27. The first variant is reported to cause non-sense-mediated decay of mRNA.
It is present in population databases (rs747058622) at a very low frequency (G=0.00002/5 (GnomAD_exomes) and G=0.000033/4 (ExAC)) and is recorded as a likely pathogenic variant in the Clinvar database (Variation ID: 264920). The second variant has not previously been reported in population databases or clinical databases and represents a null allele in the PCNT gene for which loss-of-function is a known mechanism of MPOD II disease. In this study, the detection of biallelic variants in the PCNT gene confrmed the diagnosis of MOPD Type II and presented a new phenotype, thus expanding the phenotypic spectrum of PCNT variants associated with this condition
Declarations
Ethics approval and consent to participate Ethics approval for the study was obtained by the Faculty of Medicine, University of Colombo, Ethics Review Committee, and written informed consent for genetic testing was obtained from the parents.
Consent to publish Written consent for publication was obtained from the parents.
Competing interests Authors declare that there are no competing interests.
Author details 1 Department of Anatomy, Genetics and Biomedical Informatics, Faculty of Medicine, University of Colombo, Colombo, Sri Lanka. 2 Lady Ridgeway Hospital for Children, Colombo, Sri Lanka. 3 Post Graduate Department of Bioscience, Sardar Patel University, Vallabh Vidyanagar, Gujarat, India. 4 Department of Paediatrics, Yong Loo Lin School of Medicine, National University of Singapore, Singapore, Singapore. Received: 10 November 2021 Accepted: 29 March 2022
References
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