Characteristics of Allan-Herndon-Dudley Syndrome in Chinese children: Identification of two novel pathogenic variants of the SLC16A2 gene

Abstract

ObjectiveThe aim of this study was to identify causative variants associated with Allan-Herndon-Dudley syndrome (AHDS) in two unrelated Chinese families, and to determine their potential pathogenicity. We also summarized the core clinical symptoms of AHDS by reviewing the related literature.MethodsGenomic DNA was isolated from the peripheral blood of AHDS patients and their family members. Whole exome sequencing (WES) was performed on the proband from each family to identify the candidate variants. Subsequently, Sanger sequencing was used to verify the identified candidate variants and to assess co-segregation among the available family members. In silico prediction combined with 3D protein modeling was conducted to predict the functional effects of the variants on the encoded protein.ResultsTwo novel hemizygous variants of SLC16A2, c.1111_1112insGTCTTGT (Gly375fs*6) and c.942delA (Val315fs*28), were detected in two patients. We compared the clinical symptoms of the patients with all patients with AHDS reported in China and those reported in the literature. While both our patients presented symptoms mostly consistent with AHDS, Patient 1 had no abnormal brain structure and thyroid function, and yet showed other symptoms including lactic aciduria, conjunctival hyperemia, vomiting, laryngeal stridor, low immunoglobulin and iron levels.ConclusionsThis study expands the mutation spectrum of AHDS and has clinical value for variant-based prenatal and postnatal screening for this condition. Doctors often have difficulty identifying AHDS by using clinical symptoms. WES can help to identify specific disorder when diagnosis cannot be made based on symptoms alone.

Identification of a novel nonsense SLC16A2 gene mutation in an infant with severe neurologic phenotype: A case report

“…Due to the absence of systematic epidemiologic investigations, the precise prevalence of AHDS remains unknown [2] although it is believed to affect <1 in 1,000,000 individuals, predominantly males. [8] A study by Li et al, utilizing exome sequencing in children diagnosed with "cerebral palsy," identified the SLC16A2 variant, [10] suggesting potential cases of AHDS disguised as cerebral palsy.…”

“…Additionally, considering the number of reported cases in the literature, we hypothesized that this syndrome may be more common than previously thought. [2] MCT8 has been identified as a specific active transporter for TH, which is crucial for T3 transport across the blood-brain barrier and T3 uptake into neuronal cells. [11] Impaired thyroid hormone transport through the central nervous system during critical developmental stages, particularly in the first 2 years of life, can severely disrupt developmental processes and myelination, [9] leading to neurological deficits such as mental retardation, dystonia, spastic paraplegia, central hypotonia, and delayed verbal development.…”

“…It was later confirmed that after 60 years, mutations in the SLC16A2 gene located in the Xq13.2 region of chromosome X. [2] These mutations lead to MCT8 deficiency, hindering the transport of TH across the blood–brain barrier, resulting in inadequate neural TH supply. AHDS presents with a diverse and varied clinical spectrum and is characterized predominantly by neurological and endocrine symptoms.…”

“…[1] MCT8 is a protein composed of 539 amino acids encoded by SLC16A2 , which spans 6 exons and 5 introns. [2] Structurally, MCT8 comprises 12 transmembrane domains with intracellular amino-terminal and carboxy-terminal domains. Its expression is widespread across various tissues including the brain, heart, liver, kidney, intestine, placenta, and thyroid.…”

Proteome Analysis of Thyroid Hormone Transporter Mct8/Oatp1c1-Deficient Mice Reveals Novel Dysregulated Target Molecules Involved in Locomotor Function

“…Yet, the RNA sequencing of cerebral and striatal tissues of postnatal DKO mice revealed a significant number of dysregulated genes that do not overlap with those seen in mice, which were rendered systemically hypothyroid by an anti-thyroid drug treatment [16]. Likewise, the clinical profile of AHDS does not fully recapitulate that of patients with neurological cretinism, which is caused by a lack of TH supply during prenatal stages [17]. It is therefore reasonable to assume that specific brain regions and/or cell types rely, to a different extent, on MCT8-mediated TH transport and that other, yet unknown TH transporters may be able to compensate for the absence of MCT8 in certain cell types and developmental stages [5].…”