Department of Paediatrics, Schulich School of Medicine and Dentistry, Western University, London, ON, Canada.
Medical Genetics Program of Southwestern Ontario, London Health Sciences Centre, London, ON, Canada.
Genet Med. 2021 Jul;23(7):1234-1245. doi: 10.1038/s41436-021-01129-6. Epub 2021 Apr 6.
Proline Rich 12 (PRR12) is a gene of unknown function with suspected DNA-binding activity, expressed in developing mice and human brains. Predicted loss-of-function variants in this gene are extremely rare, indicating high intolerance of haploinsufficiency.
Three individuals with intellectual disability and iris anomalies and truncating de novo PRR12 variants were described previously. We add 21 individuals with similar PRR12 variants identified via matchmaking platforms, bringing the total number to 24.
We observed 12 frameshift, 6 nonsense, 1 splice-site, and 2 missense variants and one patient with a gross deletion involving PRR12. Three individuals had additional genetic findings, possibly confounding the phenotype. All patients had developmental impairment. Variable structural eye defects were observed in 12/24 individuals (50%) including anophthalmia, microphthalmia, colobomas, optic nerve and iris abnormalities. Additional common features included hypotonia (61%), heart defects (52%), growth failure (54%), and kidney anomalies (35%). PrediXcan analysis showed that phecodes most strongly associated with reduced predicted PRR12 expression were enriched for eye- (7/30) and kidney- (4/30) phenotypes, such as wet macular degeneration and chronic kidney disease.
These findings support PRR12 haploinsufficiency as a cause for a novel disorder with a wide clinical spectrum marked chiefly by neurodevelopmental and eye abnormalities.
富含脯氨酸蛋白 12（PRR12）是一个功能未知的基因，具有潜在的 DNA 结合活性，在发育中的小鼠和人类大脑中表达。该基因预测的功能丧失变异极其罕见，表明其单倍体不足的容忍度很高。
先前描述了三个具有智力障碍和虹膜异常且存在截断性新生 PRR12 变异的个体。我们添加了 21 名通过匹配平台鉴定出具有类似 PRR12 变异的个体，使总数达到 24 名。
我们观察到 12 个移码、6 个无义、1 个剪接位点和 2 个错义变异，以及 1 名患者存在涉及 PRR12 的大片段缺失。3 名患者存在其他遗传发现，可能会混淆表型。所有患者均存在发育障碍。在 12/24 名个体（50%）中观察到可变的结构性眼部缺陷，包括无眼症、小眼球症、视网膜裂孔、视神经和虹膜异常。其他常见特征包括肌张力低下（61%）、心脏缺陷（52%）、生长不良（54%）和肾脏异常（35%）。PrediXcan 分析显示，与预测的 PRR12 表达降低最相关的 phecodes 与眼部（7/30）和肾脏（4/30）表型富集，例如湿性黄斑变性和慢性肾病。
这些发现支持 PRR12 单倍体不足是一种新疾病的原因，其临床表型广泛，主要表现为神经发育和眼部异常。
