Alazami syndrome is a neurodevelopmental disorder characterized by postnatal growth retardation, moderate to severe intellectual disability, and facial dysmorphology. It is caused by biallelic variants in the transcriptional regulator La ribonucleoprotein 7 (LARP7), where frameshift variants accounted for the majority of cases. The current study presents 7 new patients, including 3 males and 4 females from 3 unrelated families. Careful and thorough clinical examination identified novel oro-dental disease abnormalities, including a prominent premaxilla and enamel defects. The detected variants (c.1113_1116del, c.997 + 2T > C and c.518T > C) were not reported in the previous studies. The substitution c.518T > C represented the second missense variant to be identified in patients with Alazami syndrome. Male patients from the three families fulfilled ≥ 2 clinical warning signs of primary immunodeficiency. Lymphocyte subset counts and immunoglobulin levels were estimated in patients from two families. The values were within reference ranges, with only minor non-significant alterations in cytotoxic T-cell counts. A functional assay of B lymphocyte response was performed in one family, demonstrating impaired Streptococcus pneumoniae IgG antibody production following Pneumovax vaccination in the male patient, while his female sibling mounted an adequate response. In conclusion, the disease has a wide range of symptoms, which vary greatly among the affected patients. Our study expanded the clinical and molecular spectrum of the disorder and highlighted immunodeficiency as an underrecognized disease feature, potentially with a male sex predilection.

Enhanced P-TEFb activity is thought to promote cell proliferation by increasing the transcriptional output of RNA polymerase II. The 7SK snRNP complex, which contains LARP7 and HEXIM1, sequesters and inhibits most cellular P-TEFb to prevent premature transcription elongation. Paradoxically, instead of exerting overgrowth effects, biallelic inactivation of LARP7 is linked to Alazami syndrome, a human neurodevelopmental disorder characterized by growth restriction and cognitive impairment. Here, we report that conditional ablation of either Larp7 or Hexim1 in the murine brain reduces the size and impairs the function of the hippocampal dentate gyrus during the neonatal period. Functional analyses reveal that increased P-TEFb activity enhances self-renewal transcriptional programs in transit-amplifying neuronal progenitor cells to limit neurogenesis in developing dentate gyri. These results demonstrate that dysregulated subtissular stem cell dynamics can reconcile increased P-TEFb activity with reduced organ growth, and suggest a translational opportunity for repurposing P-TEFb inhibitors to treat medical conditions affecting dentate gyrus size and function.

Preimplantation genetic testing for monogenic disorders (PGT-M) in conjunction with in vitro fertilization (IVF) has dramatically improved the ability to eliminate the development of genetic disorders among newborns. The incorporation of Sanger sequencing with PGT-M has enhanced accurate diagnosis and decreased the risk of developing genetic disorders. A total of 295 embryos were collected from 47 IVF cases, and purification was performed after extraction; spectrophotometric analysis with a Nanodrop was conducted to measure the concentration and purity of total DNA. The sequencing data were obtained from blastomere cells, which were subsequently lysed, after which the DNA was amplified by multiple displacement amplification (MDA) and analysed for the presence of single-gene disorders. The frequency of various genetic disorders indicates the number of cases associated with a specific disorder. Beta thalassaemia was the most common disorder, followed by phenylketonuria (PKU) and mucopolysaccharidosis type II (Hunter syndrome); Alazami syndrome, deafness 2, and Ehlers-Danlos syndrome each occurred only once. This study demonstrates the first step in our area to implement the Sanger sequencing technique with PGT-M before oocyte retrieval. The primary goal was to combine this novel method with clinical practices and reveal the possible factors that may impact the success of the IVF procedure.

Introduction: Biallelic pathogenic variants in LARP7 result in Alazami syndrome, which is characterized by global developmental delay, cognitive dysfunction, and dysmorphic features. Cardiac and skeletal phenotypes are reported in about 30% of individuals. We report three new individuals with Alazami syndrome and functional characterization of LARP7 variants in this study. Materials and Methods: We reviewed electronic patient charts. We applied the American College of Medical Genetics and Genomics and the Association for Molecular Pathology variant classification algorithms. We performed a 3D protein modeling tool for in silico prediction and functional characterization of LARP7 variants using qPCR gene expression experiments. We reviewed the medical literature for Alazami syndrome and LARP7. Results: We report three individuals from two unrelated families with characteristic phenotypes suggestive of Alazami syndrome. We identified a homozygous novel missense LARP7 likely pathogenic variant (p.Asp54Val) in Family 1 and a homozygous novel pathogenic LARP7 variant (p.Lys219Glu∗) in Family 2 using clinical exome sequencing. 3D protein modeling showed large structural changes for both variants compared to wildtype. The functional characterization showed a statistically significant difference in LARP7 expression between affected individuals and wildtype control. We report phenotypic variability within the same family that the cardiac phenotype was only present in Family 1, Case 2. There were < 60 individuals with Alazami syndrome reported to date. Conclusion: We report three new individuals with Alazami syndrome and two novel variants in LARP7. We report the first missense LARP7 variant associated with Alazami syndrome. We report the protein 3D structure of LARP7 variants. We show a relationship between the p.Asp54Val LARP7 variant and LARP7 expression levels. We think that this could be due to abnormal RNA binding of LARP7 as per the 3D protein modeling prediction tool.

Alazami syndrome is a rare autosomal recessive disorder characterized by primordial dwarfism, intellectual disability, and distinct facial features, primarily caused by biallelic mutations in the LARP7 gene. Osteo-oto-hepato-enteric (O2HE) syndrome is another rare autosomal recessive disorder resulting from mutations in the UNC45A gene, presenting with congenital diarrhea, neonatal cholestasis, deafness, and bone fragility. We report a unique case of an 11-month-old male patient exhibiting clinical features consistent with Alazami syndrome, including developmental delay, intellectual disability, and characteristic facial dysmorphisms (triangular face, deep-set eyes, and prominent forehead). Genetic analysis revealed a single pathogenic variant in the LARP7 gene inherited from the father, which is atypical for an autosomal recessive condition. Additionally, the patient presented with features of O2HE syndrome and was found to carry compound heterozygous mutations in the UNC45A gene. The presence of only one LARP7 variant suggests an alternative genetic mechanism, such as uniparental disomy (UPD) or a second undetected variant. This case challenges the conventional autosomal recessive inheritance model of Alazami syndrome by presenting with a single detectable LARP7 variant. It underscores the necessity for comprehensive genetic evaluations, including investigations for UPD or structural variants, in patients with suspected Alazami syndrome but only one identified pathogenic allele. Furthermore, the co-occurrence of O2HE syndrome highlights the complexity of diagnosing patients with multiple overlapping genetic disorders. This report contributes to expanding the genetic and phenotypic spectrum of Alazami syndrome and emphasizes the importance of considering multifactorial genetic mechanisms in rare congenital disorders.