TTC14 dysfunction contributing to microcephaly and lissencephaly spectrum features through protein mislocalization and impaired RNA processing

BHLHE22 monoallelic and biallelic variants cause a neurodevelopmental disorder with agenesis of the corpus callosum, intellectual disability, abnormal muscle tone and movement abnormalities.

The data establish BHLHE22 as a previously unrecognized neurodevelopmental disease gene that results in a distinct syndrome characterised by abnormalities in brain development, cognition, tone and movement.

Identification and growth features of developmental delay with macrocephaly caused by a novel TRIO variant affecting the second SH3 domain.

BACKGROUND Trio Rho guanine nucleotide exchange factor (TRIO) encodes the guanine nucleotide exchange factor (GEF) for RHOA and RAC1 GTPases, which plays a critical role in neurodevelopment. Pathogenic variants in the TRIO gene are predominantly associated with two autosomal dominant neurodevelopmental disorders: intellectual developmental disorder 44 with microcephaly (MRD44) and intellectual developmental disorder 63 with macrocephaly (MRD63). However, the genotype-phenotype correlation of TRIO-related disorders and the impacts of TRIO variants on early-life disease progression remain unclear. METHODS In this study, we recruited a male infant with developmental delay and macrocephaly and chronologically detailed his growth from birth. Whole-exome sequencing was performed to identify genetic variants; three-dimensional protein modeling was employed to assess the pathogenicity of these variants, and previously reported TRIO variants were summarized. RESULT We identified a novel TRIO missense variant (NM_007118.4: c.7738 A > T, p.I2580F; chr5:14492781 A > T/hg19) in the patient, and the variant was positioned in the second Src homology 3 (SH3) domain. Bioinformatic and three-dimensional protein modeling evidence all support the p.I2580F variant as likely pathogenic. Additionally, we systematically collated and summarized previously reported TRIO gene variants. CONCLUSION Our findings broaden the variant landscape of TRIO, establish a correlation between macrocephaly and TRIO variants within the second SH3 domain, provide the first detailed growth chart for a patient with TRIO-associated macrocephaly, and deepen our understanding of developmental impairments attributed to TRIO variants.

Comprehensive Transcriptomic and Proteomic Profiling of CILD40 with Novel Compound Heterozygous Mutations of DNAH9

Plasma proteomic analysis of patients with CILD40 identified significant enrichment of pathways related to platelet activation, complement and coagulation cascades and differential signatures in CILD40, highlighting the potential of plasma proteomics for understanding distinct pathogenic mechanisms across PCD subtypes.

A Newly Identified YIF1B Frameshift Variant Causing Kaya-Barakat-Masson Syndrome.

BackgroundKaya-Barakat-Masson syndrome (KABAMAS) is a recently described autosomal recessive neurodevelopmental disorder caused by biallelic pathogenic variants in YIF1B, a gene crucial for trafficking between the endoplasmic reticulum and the Golgi apparatus. Disruption of this pathway leads to Golgi disorganization and neuronal dysfunction, resulting in severe developmental delay, visual impairment, and progressive spasticity.Case PresentationWe report an 11-month-old Turkish girl with profound developmental delay, absent head control, poor feeding, laryngomalacia and cortical visual impairment. Brain magnetic resonance imaging (MRI) revealed corpus callosum thinning and mild ventriculomegaly. Comprehensive metabolic investigations were unrevealing. Whole exome sequencing analysis identified a novel homozygous YIF1B frameshift variant, c.440_441delinsA (p.Ala147Aspfs*51), predicted to cause loss of function.ConclusionThis case broadens the mutational spectrum of YIF1B-related disease and highlights the distinctive clinical pattern of KABAMAS. Recognition of the combination of developmental delay, cortical visual loss, and normal metabolic studies should prompt early genetic analysis. Timely molecular diagnosis enables accurate counseling and multidisciplinary management for affected families.

Biallelic SLC20A2 loss-of-function in severe early-onset neurodevelopmental disorder with brain calcification.

Findings support a dose-dependent SLC20A2 disease spectrum and expand the phenotype associated with biallelic loss of function from primary brain calcification toward severe early-onset neurodevelopmental disorder with prominent vascular and leptomeningeal calcification.

PIK3CA in-frame deletion-activated PI3K/AKT signaling pathway drives macrodactyly.