Clinical presentation and molecular characterization of a novel patient with variant POC1A-related syndrome
Clinical presentation and molecular characterization of a novel patient with variant POC1A-related syndrome
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DOI：
10.1111/cge.13911
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发表时间：
2021-01-13
影响因子：
3.5
通讯作者：
Grammatico, Paola
中科院分区：
文献类型：
--
作者：
Majore, Silvia;Agolini, Emanuele;Grammatico, Paola
POC1A 的双等位基因致病性变异导致 SOFT（身材矮小、甲发育不良、面部畸形和毛发稀少）和变异 POC1A 相关 (vPOC1A) 综合征。目前仅在两个不相关的受试者中描述了后者，它与落在外显子 10 中的有限范围的变异相关，而该变异在特定的 POC1A mRNA 中自然会被跳过。在患有 vPOC1A 综合征的个体中，从该转录物中合成一定量的 POC1A 同种型被认为是这种基因型-表型相关性的可能解释。在这里，我们阐述了一名女性的临床和分子发现，该女性因 POC1A 外显子 10 中的反复移码变异和外显子 9 中的新变异而成为复合杂合子。该女性的表型特征包括严重的高胰岛素血脂异常、黑棘皮病、中度生长受限和畸形。这些表现与之前发表的两名 vPOC1A 综合征个体的临床特征重叠。对外周血的 RT-PCR 分析以及随后对获得的扩增子进行测序证明了多种 POC1A 替代转录物，这些转录物在先证者、健康母亲和对照中表达。我们阐述了两个 POC1A 识别变异的可能后果，试图解释 vPOC1A 综合征的多效性。
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.