FBXO28 is a critical gene of the 1q41q42 microdeletion syndrome

Autor: Virginia Vicenzi, Matteo Cassina, Chiara Rigon, Alberto Casarin, Leonardo Salviati, Maurizio Clementi
Rok vydání: 2014
Předmět:
Zdroj: American journal of medical genetics. Part A. 167(6)
ISSN: 1552-4833
Popis: Au et al. [2014] reported on a girl with a 590 Kb deletion within chromosome 1q41q42 and suggested that FBXO28 is a major gene contributing to the neurodevelopmental, epileptic, and dysmorphologic phenotype of patients with 1q41q42 microdeletion syndrome [Shaffer et al., 2007; Rosenfeld et al., 2011]. In our Clinical Genetics Unit, we are following up a boy carrying a de novo 286.6 Kb deletion on chromosome 1q42.11q42.12 in which the proximal breakpoint includes the last exon of the FBXO28 gene. The deletion, detected by array-CGH analysis and refined by quantitative PCR, does not include other genes of the smallest region of overlap that has been previously identified among patients with 1q41q42 microdeletions [Shaffer et al., 2007; Rosenfeld et al., 2011]. Moreover, it involves the same additional genes included in the deletion reported by Au et al. (DEGS1, NVL, MIR320B2, CNIH4, WDR26, MIR4742) with the exception of CNIH3. The array-CGH analysis was carried out using the Agilent Human Genome CGH Microarray Kit 244 A. The proximal breakpoint of the deletion mapped between nucleotides 224,340,896 and 224,349,658, while the distal breakpoint mapped between nucleotides 224,636,258 and 224,646,322 (NCBI Build 37.1, Fig. 1). No other abnormalities were observed, excluding well-known benign copy number variations. Real-time quantitative PCR assay targeting exon 4, exon 5, and three regions of the 3’UTR of the FBXO28 gene was used to further refine the proximal breakpoint of the rearrangement. The analysis was performed on a RotorGene 6000 (Corbett Research, Mortlake, Australia) as previously described [Vecchi et al., 2011]. DNA samples from two healthy subjects were used as negative controls. The analysis revealed a deletion of the exon 5 and the 3UTR of the FBXO28 gene, while the exon 4 quantification was comparable with those of controls (Fig. 2). The patient was referred to our Institution because of developmental delay, absent speech, and seizures. He is the second-born child of healthy, nonconsanguineous parents, with an unremarkable family history. He was born at gestational week 41 after an uncomplicated pregnancy. Birth weight was 3,700 g (50th–75th centile), length was 51 cm (50th centile) and head circumference was 37.3 cm (90th centile). At birth, bilateral camptodactyly and unilateral inguinal hernia were observed. Between 18 months and 3 years of age he had five episodes of generalized febrile seizures without the evidence of EEG abnormalities. Afebrile generalized tonic–clonic seizures appeared at 6 years and slow EEG anomalies on the anterior regions were observed. Seizures were completely controlled with Valproic acid therapy. The brain MRI detected mild enlargement of the frontal horns of the lateral ventricles and a multicystic pineal gland. Neurological evaluations detected mild hypertonia with brisk reflexes. Feeding difficulties and sleep disturbance were not reported. Physical examination at 10 years (Fig. 3) revealed a head circumference of 56 cm (>97th centile), frontal bossing, dolichocephaly, wide mouth, thin vermilion of the upper lip, widely spaced teeth, and gingival hyperplasia. Cutis marmorata, generalized joint laxity, camptodactyly of the 4th and 5th fingers, tapering fingers, hallux valgus, and thin and fragile nails of both fingers and toes were also observed. Weight was 25 kg (3rd centile) and height was 132 cm (10th–25th centile). He could speak less than 20 words. Our patient and the one described by Au et al. [2014] shared several characteristic features of the 1q41q42 microdeletion syndrome, including intellectually disability, language impairment, and epilepsy. Moreover, both patients had a distinctive facial phenotype that was already recognizable in some of the previously reported patients carrying larger 1q41q42 deletions; dysmorphic features included a slightly coarse face with widely spaced eyes, broad mouth, widely spaced teeth, and gingival hyperplasia. Cutis How to Cite this Article: Cassina M, Rigon C, Casarin A, Vicenzi V, Salviati L, Clementi M. 2015. FBXO28 is a critical gene of the 1q41q42 microdeletion syndrome.
Databáze: OpenAIRE
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