Human development is a complex process that requires precise control of gene expression through regulatory proteins. Recently, heterozygous variants in PRR12, encoding a proline-rich regulatory protein, were found to cause a variable phenotype involving developmental delay/cognitive impairment, neuropsychiatric diagnoses, structural eye anomalies, congenital heart and kidney defects, and poor growth. QSER1, encoding glutamine- and serine-rich protein 1, represents a paralog of PRR12 that shares 28% overall identity at the protein level and stronger conservation (43%) in the C-terminal region. QSER1 deficiency in human embryonic stem cells causes hypermethylation of many key transcription factor genes, implicating it in the development of multiple organs. Here, we present three unrelated individuals with neurodevelopmental phenotypes, variable other multisystem anomalies, and heterozygous variants in QSER1. This includes two novel de novo frameshift alleles (p.(Lys1565Argfs∗36) and p.(Phe896fs∗28)) and one ultra-rare canonical splice site variant resulting in a combination of abnormal transcripts, frameshift (p.(Glu1393Glyfs∗26)), and in-frame deletion of a conserved amino acid (p.(Glu1393del)), supported by in silico predictions and minigene assays. In situ hybridization revealed dynamic and broad expression of qser1 in zebrafish embryos, including a strong presence in the developing brain. These data suggest a possible role for QSER1/qser1 in vertebrate development and human disease.

SHORT syndrome is a rare genetic multisystemic disorder caused by a loss-of-function mutation in the phosphoinositide-3-kinase regulatory subunit 1 (PIK3R1) gene. The disease's acronym represents its key features: short stature, hyperextensibility, ocular depression, Rieger anomaly, and teeth delay. Insulin resistance, hyperglycemia, and diabetes mellitus are common endocrinological manifestations of this condition. Currently, there are no established guidelines for the treatment of diabetes in SHORT syndrome patients. In this report, we describe a young adult male patient of Chinese descent with atypical diabetes mellitus associated with SHORT syndrome. This case was challenging due to the patient's young-onset diabetes and poor diabetes control, complicated by insulin resistance from lipodystrophy, and a strong aversion to insulin injections. By utilizing a combination of oral anti-glycemic agents with complementary mechanisms of action (metformin, sodium-glucose co-transporter 2 (SGLT-2) inhibitors, sulfonylureas, thiazolidinediones, and GLP-1 agonists), insulin therapy was delayed. The patient's blood glucose levels improved significantly, with HbA1c decreased from 14% to 8.8% within 6 months of starting the multi-agent regimen, and further improved to 7.4% with a fasting plasma glucose of 4.8 mmol/L. With an oral medication regimen that the patient found acceptable, both his quality of life and adherence to treatment improved. These findings provide useful insights into tailoring an individualized diabetes treatment plan.

A 33-year-old man presented with short stature, thin build, hearing impairment, Rieger anomaly, and a history of inguinal hernia. He also exhibited characteristic facies, including a triangular face with a small chin, deeply set eyes, and low-set ears. He was born with intrauterine growth restriction and developed diabetes during adolescence, requiring high-dose insulin therapy. For 19 years, an accurate diagnosis was not made. We performed direct sequencing of the insulin receptor gene and exons 11-16 of the PIK3R1 gene, identifying a c.1957A>T mutation (p.Lys653*) in the PIK3R1 gene, which confirmed a diagnosis of SHORT syndrome. Suspecting SHORT syndrome in individuals who exhibit some of its typical symptoms may facilitate an accurate diagnosis and enable effective management of this condition.

Nineteen-year follow-up after initial examination on patients with Axenfeld-Rieger anomaly or syndrome (ARAS) and coexisting Fuchs' endothelial dystrophy (FED). All individuals had previously been tested positive for the PITX2 (g.20 913 G>T) mutation. Additionally, we addressed their descendants for phenotype and genotype examination to determine their penetrance into the next generations. Twenty-nine patients (9 patients and 20 of their descendants) participated in this prospective observational study. Nine patients were examined and tested positive for the PITX variant (g.20 913 G>T) in our previous study in 2001. Fourteen descendants were genetically and clinically examined. Six descendants were not available for clinical examination but donated saliva samples for genetic analysis. Ophthalmic examination was performed, consisting of visual acuity (VA) testing, applanation tonometry, gonioscopy, and anterior segment and central fundus biomicroscopy. Peripapillary optical coherence tomography (pOCT) was performed, and endothelial cell density (ECD) and central corneal thickness (CCT) were measured. Clinical disease progression in patients with a positive PITX2 mutation, genetic defect transmission, and clinical penetrance in subsequent third to sixth generations were the main outcome measures. Ten out of twenty descendants tested positive for the PITX2 variant (g.20 913 G>T). Eight were identified as being affected by ARAS. FED was found in six patients. All of them showed ARAS. Third generation patients (mean age 82) progressed significantly in both coexisting diseases. Four of six eyes ended up in corneal edema, with VA below 0.2. Glaucoma assessment was compromised due to corneal edema. Fourth generation patients (mean age 43) showed a mean CCT of 611 µm, ECD of 1230, and intraocular pressure (IOP) of 17.5 mmHg and thinning of the peripapillary nerve fiber layer. One eye was newly diagnosed with glaucoma, elevated IOP, and mild corneal edema. Fifth generation patients (mean age 27) presented with a mean CCT of 564 µm, ECD of 2802, and IOP of 14.4 mmHg. Genetic analysis confirmed the PITX2 (g.20 913 G>T) mutation was associated with Axenfeld-Rieger and FED in 10 of 20 descendants in this family. This matches the autosomal dominant inheritance pattern with a probability of 50%. Glaucoma and corneal decompensation were progressive over 19 years, with variable expression and early onset in subsequent pedigree members. Verlaufsbeurteilung nach 19 Jahren bei Patienten mit Axenfeld-Rieger-Anomalie oder -Syndrom (ARAS) und Fuchs-Endotheldystrophie (FED). Bei allen wurde vorangehend die PITX2-Variante (g.20 913 G>T) nachgewiesen. Wir untersuchten des Weiteren Genotyp und Phänotyp der Nachkommen, um das Vererbungsmuster festzustellen. 29 Patienten (9 Patienten und 20 Nachkommen) wurden in diese prospektive Beobachtungsstudie eingeschlossen. 9 Patienten wurden bereits in einer vorhergehenden Studie positiv auf die PITX-Variante (g.20 913 G>T) getestet. 14 Nachkommen wurden genetisch und klinisch untersucht. 6 Nachkommen wurden genetisch untersucht, ohne an einer klinischen Untersuchung teilzunehmen. Die Untersuchung umfasste Visus (VA), Applanationstonometrie, Gonioskopie, Biomikroskopie der Vorderkammer und des zentralen Fundus. Eine optische Kohärenztomografie der Papille (pOCT) wurde durchgeführt. Endothelzelldichte (ECD) und zentrale Hornhautdicke (CCT) wurden gemessen. Eine klinische Progression in Patienten mit PITX2-Mutation, genetisches und morphologisches Vererbungsmuster wurden in 4 Generationen (3. – 6. Generation) untersucht. Die PITX2-Variante (g.20 913 G>T) ließ sich in 10 von 20 Nachkommen bestätigen. Bei 7 Patienten ließ sich das ARAS in der klinischen Untersuchung zeigen. FED wurde in 6 Patienten nachgewiesen. Die Patienten der 3. Generation (Durchschnittsalter 82 Jahre) zeigten eine deutliche Progression beider Erkrankungen. Vier von 6 Augen zeigten ein korneales Ödem mit einem Visus < 0,2. Aufgrund der kornealen Dekompensation war eine Beurteilung des Glaukoms erschwert. Die Patienten der 4. Generation (Durchschnittsalter 43 Jahre) wiesen eine mittlere Hornhautdicke von 611 µm, eine Endothelzelldichte von 1230 Zellen/mm2 und einen durchschnittlichen Intraokulardruck von 17,5 mmHg auf. Kohärenztomografisch konnte eine reduzierte retinale Nervenfaserschicht gezeigt werden. Die Patienten der 5. Generation (Durchschnittsalter 27 Jahre) zeigten eine mittlere Hornhautdicke von 564 µm, eine Endothelzelldichte von 2802 Zellen/mm2 und einen durchschnittlichen Intraokulardruck von 14,4 mmHg. Die genetische Analyse bestätigte das Vorliegen der PITX2-Mutation (g.20 913 G>T) in Zusammenhang mit Axenfeld-Rieger und Fuchs-Endotheldystrophie in 10 von 20 Nachkommen in einem Familienstammbaum. Aufgrund des autosomal-dominanten Vererbungsmusters besteht eine Wahrscheinlichkeit von 50%. Ein Fortschreiten von glaukomatösen Veränderungen wie auch kornealer Dekompensation konnte über einen Verlauf von 19 Jahren gezeigt werden mit frühzeitiger Manifestation und variabler, klinischer Ausprägung in den Nachkommen.

Development of the anterior segment of the eye requires reciprocal sequential interactions between the arising tissues, facilitated by numerous genetic factors. Disruption of any of these processes results in congenital anomalies in the affected tissue(s) leading to anterior segment disorders (ASD) including aniridia, Axenfeld-Rieger anomaly, congenital corneal opacities (Peters anomaly, cornea plana, congenital primary aphakia), and primary congenital glaucoma. Current understanding of the genetic factors involved in ASD remains incomplete, with approximately 50% overall receiving a genetic diagnosis. While some genes are strongly associated with a specific clinical diagnosis, the majority of known factors are linked with highly variable phenotypic presentations, with pathogenic variants in FOXC1, CYP1B1, and PITX2 associated with the broadest spectrum of ASD conditions. This review discusses typical clinical presentations including associated systemic features of various forms of ASD; the latest functional data and genotype-phenotype correlations related to 25 ASD factors including newly identified genes; promising novel candidates; and current and emerging treatments for these complex conditions. Recent developments of interest in the genetics of ASD include identification of phenotypic expansions for several factors, discovery of multiple modes of inheritance for some genes, and novel mechanisms including a growing number of non-coding variants and alleles affecting specific domains/residues and requiring further studies.