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Updated: May 21, 2026
Targeted Next-generation Sequencing and Bioinformatics Pipeline to Evaluate Genetic Determinants of Constitutional Disease
Published on: April 4, 2018
Clinical and functional characterization of a patient carrying a compound heterozygous pericentrin mutation and a
Eva Müller1, Desiree Dunstheimer, Jürgen Klammt
1Pediatric Research Center, University Hospital for Children and Adolescents, Leipzig, Germany.
Insights
Genetic analysis revealed compound heterozygous PCNT mutations cause MOPD II, a rare dwarfism syndrome. This highlights the importance of comprehensive genetic evaluation for accurate diagnosis in growth disorders.
Area of Science:
- Genetics
- Endocrinology
- Pediatrics
Background:
- Longitudinal growth is a complex process influenced by genetics and endocrine factors, impacting cellular functions in growth centers.
- Small for gestational age (SGA) infants may experience severe postnatal growth retardation, sometimes associated with skeletal dysplasia, microcephaly, and other conditions.
Observation:
- A patient presented with SGA, severe proportionate postnatal growth retardation, skeletal dysplasia, microcephaly, and moyamoya disease.
- Initial genetic testing identified a novel heterozygous IGF1R mutation, but it did not fully explain the phenotype or co-segregate with the condition.
Findings:
- Further genetic screening identified compound heterozygous mutations in the PCNT gene (p.[Arg585X];[Glu1774X]).
- These PCNT mutations were definitively linked to the patient's phenotype, leading to a diagnosis of Majewski Osteodysplastic Primordial Dwarfism type II (MOPD II).
Implications:
- This case underscores the critical need for thorough genetic investigation beyond initial findings, especially when a single mutation does not fully account for a complex phenotype.
- Accurate diagnosis of rare genetic disorders like MOPD II relies on careful correlation of sequence aberrations with clinical presentation and potentially identifying multiple causative variants.
Abstract:
Intrauterine and postnatal longitudinal growth is controlled by a strong genetic component that regulates a complex network of endocrine factors integrating them with cellular proliferation, differentiation and apoptotic processes in target tissues, particularly the growth centers of the long bones. Here we report on a patient born small for gestational age (SGA) with severe, proportionate postnatal growth retardation, discreet signs of skeletal dysplasia, microcephaly and moyamoya disease. Initial genetic evaluation revealed a novel heterozygous IGF1R p.Leu1361Arg mutation affecting a highly conserved residue with the insulin-like growth factor type 1 receptor suggestive for a disturbance within the somatotropic axis. However, because the mutation did not co-segregate with the phenotype and functional characterization did not reveal an obvious impairment of the ligand depending major IGF1R signaling capabilities a second-site mutation was assumed. Mutational screening of components of the somatotropic axis, constituents of the IGF signaling system and factors involved in cellular proliferation, which are described or suggested to provoke syndromic dwarfism phenotypes, was performed. Two compound heterozygous PCNT mutations (p.[Arg585X];[Glu1774X]) were identified leading to the specification of the diagnosis to MOPD II. These investigations underline the need for careful assessment of all available information to derive a firm diagnosis from a sequence aberration.
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