Clinical presentation and molecular characterization of a novel patient with variant POC1A‐related syndrome

Abstract

Biallelic pathogenic variants in POC1A result in SOFT (Short‐stature, Onychodysplasia, Facial‐dysmorphism, and hypoTrichosis) and variant POC1A‐related (vPOC1A) syndromes. The latter, nowadays described in only two unrelated subjects, is associated with a restricted spectrum of variants falling in exon 10, which is naturally skipped in a specific POC1A mRNA. The synthesis of an amount of a POC1A isoform from this transcript in individuals with vPOC1A syndrome has been believed as the likely explanation for such a genotype–phenotype correlation. Here, we illustrate the clinical and molecular findings in a woman who resulted to be compound heterozygous for a recurrent frameshift variant in exon 10 and a novel variant in exon 9 of POC1A. Phenotypic characteristics of this woman included severe hyperinsulinemic dyslipidemia, acanthosis nigricans, moderate growth restriction, and dysmorphisms. These manifestations overlap the clinical features of the two previously published individuals with vPOC1A syndrome. RT‐PCR analysis on peripheral blood and subsequent sequencing of the obtained amplicons demonstrated a variety of POC1A alternative transcripts that resulted to be expressed in the proband, in the healthy mother, and in controls. We illustrate the possible consequences of the two POC1A identified variants in an attempt to explain pleiotropy in vPOC1A syndrome.

Identification of SOFT syndrome caused by a pathogenic homozygous splicing variant of POC1A: a case report

“…Giorgio E et al suggested that the POC1A gene was a gene with pleiotropic effects, and variants affecting exon 10 only could cause variant POC1A-related (vPOC1A) syndrome instead of typical SOFT syndrome, whose main clinical features included an extreme dyslipidemia with insulin resistance and acanthosis nigricans, because variants restricted to exon 10 of the POC1A gene affected only two of the three mRNA isoforms, leaving a functional isoform [ 7 ]. To date, three vPOC1A syndrome individuals had been reported [ 4 , 7 , 12 ]. The splicing variant detected in our patient has been proven to cause exon 9 skipping which are necessary in all isoforms and affect WD40 domain integrity.…”

“…Therefore, SOFT syndrome could be classified as a type of ciliopathy. To our best knowledge, only 13 variants of POC1A gene have been reported until now, including 7 missense mutations, 2 nonsense mutations and 4 frameshift mutations [1][2][3][4][5][6][7][8][9][10][11][12] (Fig. 3).…”

“…POC1A gene has pleiotropic effects, because truncating variants locating in exon 10 could cause variant POC1A-related (vPOC1A) syndrome, whose main clinical features included an extreme dyslipidemia with insulin resistance, acanthosis nigricans and short stature. To date, only 15 families with molecularly confirmed variants in POC1A gene have been reported [1][2][3][4][5][6][7][8][9][10][11][12]. POC1A gene encodes the POC1 centriolar protein A, which is one of the two proteome of centriole 1 (POC1) proteins in humans.…”

Biallelic POC1A variants cause syndromic severe insulin resistance with muscle cramps

“…Since these initial reports ( 1 , 2 , 3 ), 12 additional affected kindreds have been described ( 7 , 8 , 9 , 10 , 11 , 12 , 13 , 14 , 15 , 16 ). In addition to the cardinal syndromic features, three of 31 patients reported to date also manifested severe dyslipidaemic insulin resistance (IR) ( 7 , 11 , 16 ).…”

POC1A, a Novel Prognostic Biomarker that Correlated With Immunosuppressive Microenvironment in Pan-cancer

“…As an important component of the centrosome, POC1A (POC1 centriolar protein homolog A), which is also called WDR51A, plays an important role in the formation and steady state of centrioles in biological processes (Keller et al,2009). Numerous studies have con rmed that POC1A is related with facial dysmorphism and hypotrichosis (SOFT) syndrome, onychodysplasia, short stature, which is associated to abnormalities in cell mitosis (Koparir et al,2015,Majore et al,2021. All these studies reveal that POC1A may play a important role in cell proliferation.…”