Mental Retardation, Autosomal Dominant 47

A number sign (#) is used with this entry because of evidence that autosomal dominant mental retardation-47 (MRD47) is caused by heterozygous mutation in the STAG1 gene (604358) on chromosome 3q22.

Clinical Features

Lehalle et al. (2017) described 13 patients from 12 unrelated families with delayed psychomotor development and intellectual disability, mostly mild to moderate, usually with delayed speech. Three patients had severe intellectual disability, including 1 born of consanguineous parents. Most of the patients were children, but 1 was aged 15 years and another 29 years. Many patients had feeding difficulties and/or gastroesophageal reflux early in life; some had mild growth retardation. The patients shared some dysmorphic features, including deep-set eyes, a wide mouth, and a high nasal bridge; these features tended to become more apparent with age. Five patients had seizures, ranging from recurrent febrile seizures to epileptic encephalopathy (1 patient). Other more variable features included hypotonia, joint hyperlaxity, autistic features, and nonspecific brain anomalies, such as cerebral atrophy. The patients were identified from several large patient pools and data sharing from worldwide research cohorts.

Cytogenetics

Lehalle et al. (2017) reported 4 unrelated patients with de novo heterozygous deletions of chromosome 3q22 including the STAG1 and PCCB (232050) genes. The deletions were found by array-CGH. The patients had intellectual disability and features similar to those observed in patients with point mutations in the STAG1 gene; however, those with larger deletions had a higher prevalence of microcephaly, which reached statistical significance.

Inheritance

The transmission pattern of MRD47 in the family reported by Lehalle et al. (2017) was consistent with autosomal dominant inheritance.

Molecular Genetics

In 6 members of a family (family 5) with MRD47, Lehalle et al. (2017) identified a heterozygous intragenic deletion within the STAG1 gene (604358.0001). The deletion, which was found by array-CGH, segregated with the disorder in the family. Whole-exome sequencing of several large patient cohorts identified 11 additional nonrecurrent de novo heterozygous missense or frameshift mutations in the STAG1 gene (see, e.g., 604358.0002-604358.0006) in 11 unrelated patients with a similar phenotype. Functional studies of the variants and studies of patient cells were not performed, but Lehalle et al. (2017) postulated that the neurodevelopmental phenotype is caused by STAG1 haploinsufficiency with a putative disruptive effect on transcriptional regulation.