RESUMEN
Alu elements are short, interspersed elements located throughout the genome, playing a role in human diversity, and occasionally causing genetic diseases. Here, we report a novel Alu insertion causing Mowat-Wilson syndrome, a rare neurodevelopmental disorder, in an 8-year-old boy displaying the typical clinical features for Mowat-Wilson syndrome. The variant was not initially detected in genome sequencing data, but through deep phenotyping, which pointed to only one plausible candidate gene, manual inspection of genome sequencing alignment data enabled us to identify a de novo heterozygous Alu insertion in exon 8 of the ZEB2 gene. Nanopore long-read sequencing confirmed the Alu insertion, leading to the formation of a premature stop codon and likely haploinsufficiency of ZEB2. This underscores the importance of deep phenotyping and mobile element insertion analysis in uncovering genetic causes of monogenic disorders as these elements might be overlooked in standard next-generation sequencing protocols.
Asunto(s)
Elementos Alu , Facies , Enfermedad de Hirschsprung , Discapacidad Intelectual , Microcefalia , Caja Homeótica 2 de Unión a E-Box con Dedos de Zinc , Humanos , Elementos Alu/genética , Microcefalia/genética , Microcefalia/patología , Masculino , Niño , Caja Homeótica 2 de Unión a E-Box con Dedos de Zinc/genética , Enfermedad de Hirschsprung/genética , Enfermedad de Hirschsprung/patología , Discapacidad Intelectual/genética , Discapacidad Intelectual/patología , Fenotipo , Mutagénesis Insercional/genética , Secuenciación de Nucleótidos de Alto Rendimiento , Exones/genéticaRESUMEN
Primrose syndrome (OMIM 259050) is a rare disorder characterised by macrocephaly with developmental delay, a recognisable facial phenotype, altered glucose metabolism, and other features such as sensorineural hearing loss, short stature, and calcification of the ear cartilage. It is caused by heterozygous variants in ZBTB20, a member of the POK family of transcription repressors. Recently, this gene was shown to have a role in skeletal development through its action on chondrocyte differentiation by repression of SOX9. We describe five unrelated patients with Primrose syndrome and distinct skeletal features including multiple Wormian bones, platybasia, bitemporal bossing, bathrocephaly, slender bones, epiphyseal and spondylar dysplasia. The radiological abnormalities of the skull and the epiphyseal dysplasia were the most consistent findings. This novel constellation of skeletal features expands the phenotypic spectrum of the disorder.
Asunto(s)
Anomalías Múltiples/patología , Huesos/anomalías , Calcinosis/patología , Enfermedades del Oído/patología , Discapacidad Intelectual/patología , Atrofia Muscular/patología , Fenotipo , Anomalías Múltiples/genética , Adolescente , Huesos/diagnóstico por imagen , Calcinosis/genética , Niño , Preescolar , Enfermedades del Oído/genética , Femenino , Humanos , Discapacidad Intelectual/genética , Masculino , Atrofia Muscular/genética , Proteínas del Tejido Nervioso/genética , Factores de Transcripción SOXB1/genética , Factores de Transcripción/genética , Adulto JovenRESUMEN
The conserved oligomeric Golgi (COG) complex is involved in intracellular vesicular transport, and is composed of eight subunits distributed in two lobes, lobe A (COG1-4) and lobe B (COG5-8). We describe fourteen individuals with Saul-Wilson syndrome, a rare form of primordial dwarfism with characteristic facial and radiographic features. All affected subjects harbored heterozygous de novo variants in COG4, giving rise to the same recurrent amino acid substitution (p.Gly516Arg). Affected individuals' fibroblasts, whose COG4 mRNA and protein were not decreased, exhibited delayed anterograde vesicular trafficking from the ER to the Golgi and accelerated retrograde vesicular recycling from the Golgi to the ER. This altered steady-state equilibrium led to a decrease in Golgi volume, as well as morphologic abnormalities with collapse of the Golgi stacks. Despite these abnormalities of the Golgi apparatus, protein glycosylation in sera and fibroblasts from affected subjects was not notably altered, but decorin, a proteoglycan secreted into the extracellular matrix, showed altered Golgi-dependent glycosylation. In summary, we define a specific heterozygous COG4 substitution as the molecular basis of Saul-Wilson syndrome, a rare skeletal dysplasia distinct from biallelic COG4-CDG.
Asunto(s)
Síndrome del Cromosoma X Frágil/genética , Transporte de Proteínas/genética , Proteoglicanos/genética , Proteínas de Transporte Vesicular/genética , Adulto , Sustitución de Aminoácidos/genética , Animales , Animales Modificados Genéticamente/genética , Línea Celular , Niño , Preescolar , Retículo Endoplásmico/genética , Matriz Extracelular/genética , Femenino , Fibroblastos/patología , Glicosilación , Aparato de Golgi/genética , Heterocigoto , Humanos , Lactante , Masculino , Pez CebraRESUMEN
A four-year-old girl was referred to a paediatric department with low height, obesity and hypothyroidism. Her paraclinical tests were characteristic with elevated P-parathyroid hormone concentration, hypothyroidism, growth hormone deficiency, abnormal phenotype with brachydactyly, tooth problems and mental retardation, which led to a suspicion of Albright's hereditary osteodystrophy (AHO). The diagnosis was verified by molecular genetic testing. Less than 1% of children with obesity have an endocrine disorder, and AHO is one of them.
