Center for Genetics and Inherited Diseases, Taibah University, Almadinah Almunwarah, Saudi Arabia.
Section of Medical Genetics, Children's Specialist Hospital, King Fahad Medical City, Riyadh, Saudi Arabia.
J Hum Genet. 2021 Jul;66(7):689-695. doi: 10.1038/s10038-021-00904-2. Epub 2021 Jan 27.
Heterozygous pathogenic variants in SLC12A2 are reported in patients with nonsyndromic hearing loss. Recently, homozygous loss-of-function variants have been reported in two patients with syndromic intellectual disability, with or without hearing loss. However, the clinical and molecular spectrum of SLC12A2 disease has yet to be characterized and confirmed. Using whole-exome sequencing, we detected a homozygous splicing variant in four patients from two independent families with severe developmental delay, microcephaly, respiratory abnormalities, and subtle dysmorphic features, with or without congenital hearing loss. We also reviewed the reported cases with pathogenic variants associated with autosomal dominant and recessive forms of the SLC12A2 disease. About 50% of the cases have syndromic and nonsyndromic congenital hearing loss. All patients harboring the recessive forms of the disease presented with severe global developmental delay. Interestingly, all reported variants are located in the c-terminal domain, suggesting a critical role of this domain for the proper function of the encoded co-transporter protein. In conclusion, our study provides an additional confirmation of the autosomal recessive SLC12A2 disease.
SLC12A2 中的杂合致病性变体已在非综合征型听力损失患者中报道。最近，在两名伴有或不伴有听力损失的综合征型智力残疾患者中已报道了纯合失活变异体。然而，SLC12A2 疾病的临床和分子谱尚未得到明确和证实。使用全外显子组测序，我们在来自两个独立家系的四名患有严重发育迟缓、小头畸形、呼吸异常和轻微畸形特征的患者中检测到纯合剪接变异体，这些患者伴有或不伴有先天性听力损失。我们还回顾了与 SLC12A2 疾病的常染色体显性和隐性形式相关的报道病例。大约 50%的病例有综合征型和非综合征型先天性听力损失。所有携带该疾病隐性形式的患者均表现为严重的全面发育迟缓。有趣的是，所有报道的变异体均位于 C 末端结构域，提示该结构域对编码共转运蛋白的正确功能至关重要。总之，本研究进一步证实了常染色体隐性 SLC12A2 疾病的存在。
