A fetal case of microphthalmia and limb anomalies with abnormal neuronal migration associated with SMOC1 biallelic variants

Anno:

2019

A fetal case of microphthalmia and limb anomalies with abnormal neuronal migration associated with SMOC1 biallelic variants

Mancini C1, Zonta A2, Botta G3, Breda Klobus A4, Valbonesi S4, Pasini B2, Giorgio E1, Viora E5, Brusco A6, Brussino A1.

Author information

1: University of Torino, Department of Medical Sciences, 10126, Torino, Italy.
2: Città Della Salute e Della Scienza University Hospital, Medical Genetics Unit, 10126, Torino, Italy.
3: Città Della Salute e Della Scienza University Hospital, Departments of Pathology, 10126, Torino, Italy.
4: Breda Genetics, Brescia, Italy.
5: Città Della Salute e Della Scienza University Hospital, Department of Gynecology and Obstetrics, Ultrasound and Prenatal Diagnosis Unit, 10126, Torino, Italy.
6: University of Torino, Department of Medical Sciences, 10126, Torino, Italy; Città Della Salute e Della Scienza University Hospital, Medical Genetics Unit, 10126, Torino, Italy. Electronic address: alfredo.brusco@unito.it.

Abstract

Microphthalmia with limb anomalies (MLA, OMIM, 206920) is a rare autosomal-recessive disease caused by biallelic pathogenic variants in the SMOC1 gene. It is characterized by ocular disorders (microphtalmia or anophtalmia) and limb anomalies (oligodactyly, syndactyly, and synostosis of the 4th and 5th metacarpals), variably associated with long bone hypoplasia, horseshoe kidney, venous anomalies, vertebral anomalies, developmental delay, and intellectual disability. Here, we report the case of a woman who interrupted her pregnancy after ultrasound scans revealed a depression of the frontal bone, posterior fossa anomalies, cerebral ventricular enlargement, cleft spine involving the sacral and lower-lumbar vertebrae, and bilateral microphthalmia. Micrognathia, four fingers in both feet and a slight tibial bowing were added to the clinical picture after fetal autopsy. Exome sequencing identified two variants in the SMOC1 gene, each inherited from one of the parents: c.709G>T - p.(Glu237*) on exon 8 and c.1223G>A - p.(Cys408Tyr) on exon 11, both predicted to be pathogenic by different bioinformatics software. Brain histopathology showed an abnormal cortical neuronal migration, which could be related to the SMOC1 protein function, given its role in cellular signaling, proliferation and migration. Finally, we summarize phenotypic and genetic data of known MLA cases showing that our case has some unique features (Chiari II malformation; focal neuropathological alterations) that could be part of the variable phenotype of SMOC1-associated diseases.