1Serviço de Genética Médica, Área da Mulher, Criança e Adolescente, Hospital Dona Estefânia, Centro Hospitalar Universitário de Lisboa Central, Lisboa, Portugal
2Serviço de Neuropediatria, Área da Mulher, Criança e Adolescente, Hospital Dona Estefânia, Centro Hospitalar Universitário de Lisboa Central, Lisboa, Portugal
3Serviço de Cardiologia Pediátrica, Hospital Santa Marta, Centro Hospitalar Universitário de Lisboa Central, Lisboa, Portugal
4CGC Genetics, Porto, Portugal
5Centro de Referência de Doenças Hereditárias do Metabolismo, Centro Hospitalar Universitário de Lisboa Central, Lisboa, Portugal
- Poster -15th International Symposium of Sociedade Portuguea de Doenças Metabólicas
- Coimbra, 14 a 16 março de 2019
Background: Unexplained developmental delay or intellectual disability is one of the most common reasons for referral to genetic counseling. Yet, in over 50% of the cases routine examination does not reveal the clinical entity. A systematic clinical approach can help to identify a genetic cause. Clinical exome sequencing has enabled a rapid progress in this field, reducing the mean cost per diagnosis and the diagnostic odyssey.
Case Report: A 2-year-old boy was referred to our genetic clinics for global development delay and autism spectrum disorder with aggressive behavior and stereotypies. At observation, it was noted mild facial dysmorphisms. Initial studies, including extensive metabolic investigation and brain MRI were not able to identify an etiology. Further cardiac evaluation revealed aortic dilation. Microarray analysis showed a 13 Kbp 5p15.33 deletion evolving CCDC127 and SDHA genes that did not correlate with the phenotype. Exome sequencing identified two compound heterozygous variants in MAN1B1 gene: c.1731C>G (p.Tys577*) and c.1976T>G (p.Phe659Cys), and an hemizygous variant in ZNF674 gene was detected: c.1512del (p.Ala505Profs*32). The first and third variants have not been reported before; they introduce premature stop codons leading to truncated proteins, being classified as likely pathogenic. The second variant has been reported in a patient with intellectual disability and in silico analysis supports its pathogenicity. Subsequent serum transferrin IEF showed a type 2 pattern, allowing to confirm a MAN1B1 defective congenital disorder of glycosylation (MAN1B1-CDG).
Comments: Congenital disorders of glycosylation (CDG) comprise a group of inborn errors of metabolism, caused by deficient protein and/or lipid glycosylation. MAN1B1 gene variants have been associated with non-syndromic autosomal recessive intellectual disability and CDG. Recent publications, have reported patients with a common MAN1B1 phenotype, comprising mild intellectual disability, truncal obesity and facial dysmorphisms. Our patient did not present with obesity, and he is the first presenting aortic dilatation. ZNF674 gene variants have been associated with X-linked intellectual disability. Here, exome sequencing led to the discovery of MAN1B1 as the culprit gene in an unsolved case of global development delay and thereby, retrospectively, diagnosed CDG. In unexplained intellectual disability, serum transferrin should be included in the first-line screening.