RESUMEN
Baratela-Scott syndrome (BSS) is a rare, autosomal-recessive disorder characterized by short stature, facial dysmorphisms, developmental delay, and skeletal dysplasia caused by pathogenic variants in XYLT1. We report clinical and molecular investigation of 10 families (12 individuals) with BSS. Standard sequencing methods identified biallelic pathogenic variants in XYLT1 in only two families. Of the remaining cohort, two probands had no variants and six probands had only a single variant, including four with a heterozygous 3.1 Mb 16p13 deletion encompassing XYLT1 and two with a heterozygous truncating variant. Bisulfite sequencing revealed aberrant hypermethylation in exon 1 of XYLT1, always in trans with the sequence variant or deletion when present; both alleles were methylated in those with no identified variant. Expression of the methylated XYLT1 allele was severely reduced in fibroblasts from two probands. Southern blot studies combined with repeat expansion analysis of genome sequence data showed that the hypermethylation is associated with expansion of a GGC repeat in the XYLT1 promoter region that is not present in the reference genome, confirming that BSS is a trinucleotide repeat expansion disorder. The hypermethylated allele accounts for 50% of disease alleles in our cohort and is not present in 130 control subjects. Our study highlights the importance of investigating non-sequence-based alterations, including epigenetic changes, to identify the missing heritability in genetic disorders.
Asunto(s)
Anomalías Múltiples/genética , Metilación de ADN/genética , Epigénesis Genética/genética , Exones/genética , Mutación , Pentosiltransferasa/genética , Expansión de Repetición de Trinucleótido/genética , Alelos , Southern Blotting , Estudios de Cohortes , Femenino , Humanos , Lactante , Recién Nacido , Masculino , Linaje , Sulfitos/metabolismo , Síndrome , UDP Xilosa Proteína XilosiltransferasaRESUMEN
This report presents the detection of a heterozygous deletion at chromosome 12q14 in three unrelated patients with a similar phenotype consisting of mild mental retardation, failure to thrive in infancy, proportionate short stature and osteopoikilosis as the most characteristic features. In each case, this interstitial deletion was found using molecular karyotyping. The deletion occurred as a de novo event and varied between 3.44 and 6 megabases (Mb) in size with a 3.44 Mb common deleted region. The deleted interval was not flanked by low-copy repeats or segmental duplications. It contains 13 RefSeq genes, including LEMD3, which was previously shown to be the causal gene for osteopoikilosis. The observation of osteopoikilosis lesions should facilitate recognition of this new microdeletion syndrome among children with failure to thrive, short stature and learning disabilities.
Asunto(s)
Deleción Cromosómica , Trastornos de los Cromosomas/genética , Cromosomas Humanos Par 12/genética , Enanismo/genética , Discapacidad Intelectual/genética , Osteopoiquilosis/genética , Anomalías Múltiples/genética , Adulto , Proteínas Portadoras/genética , Proteínas Portadoras/fisiología , Rotura Cromosómica , Trastornos de los Cromosomas/patología , Mapeo Cromosómico , Cromosomas Artificiales Bacterianos , Cromosomas Humanos Par 12/ultraestructura , Proteínas de Unión al ADN , Insuficiencia de Crecimiento/etiología , Femenino , Proteína HMGA2/genética , Proteína HMGA2/fisiología , Heterocigoto , Humanos , Lactante , Recién Nacido de Bajo Peso , Recién Nacido , Discapacidades para el Aprendizaje/genética , Masculino , Proteínas de la Membrana/deficiencia , Proteínas de la Membrana/genética , Proteínas del Tejido Nervioso/genética , Proteínas del Tejido Nervioso/fisiología , Proteínas Nucleares/deficiencia , Proteínas Nucleares/genética , Análisis de Secuencia por Matrices de Oligonucleótidos , Fenotipo , Escoliosis/genética , Eliminación de Secuencia , SíndromeRESUMEN
Characteristic features of the 12q14 microdeletion syndrome include low birth weight, failure to thrive, short stature, learning disabilities and Buschke-Ollendorff lesions in bone and skin. This report on two additional patients with this microdeletion syndrome emphasizes the rather constant and uniform phenotype encountered in this disorder and refines the critical region to a 2.61 Mb interval on 12q14.3, encompassing 10 RefSeq genes. We have previously shown that LEMD3 haploinsufficiency is responsible for the Buschke-Ollendorff lesions and now provide strong evidence that a heterozygous deletion of HMGA2 is causing the growth failure observed in this disorder. The identification of an intragenic HMGA2 deletion in a boy with proportionate short stature and the cosegregation of this deletion with reduced adult height in the extended family of the boy further underscore the role of HMGA2 in regulating human linear growth.