Polymicrogyria associated with 17p13.3p13.2 duplication: Case report and review of the literature

Abstract

We present the case of a male infant with bilateral perisylvian polymicrogyria associated with a de novo duplication of chromosome region 17p13.3p13.2. To our knowledge, this is the first report of polymicrogyria associated with the 17p13.3 contiguous gene duplication syndrome. Testing for known monogenic causes of polymicrogyria was negative and there was no clinical evidence of an acquired prenatal cause. Given the critical, dose-sensitive role that the 17p13.3 region plays in brain development, we suggest that the chromosome duplication is the most likely explanation for the polymicrogyria. Clinical and functional studies have demonstrated deleterious effects of increased LIS1 expression on the developing brain and the contribution of YWHAE to the brain phenotype of the 17p13 duplication syndrome. There is also evidence that CRK, the other candidate gene in this region, via interaction with LIS1, plays a critical role in cortical development. In addition to LIS1, YWHAE and CRK, our patient's chromosome duplication involves at least 100 other genes, less than half of which are annotated at the time of writing. It is expected that the ongoing use of chromosome microarray and next-generation sequencing to investigate the genetic causes of brain malformations will continue to extend our understanding of the 17p13 region and of the contributions of the genes in this region to cortical development.

Introduction

We present the case of a male infant with bilateral perisylvian polymicrogyria associated with a de novo duplication of chromosome region 17p13.3p13.2. 17p13.3 is a gene-rich chromosome region containing at least two critical genes, PAFAH1B1 (LIS1) and YWHAE, and a third gene of interest CRK. Deletions of this region are very well characterized and cause the classical lissencephaly spectrum of disorders. Duplication of the 17p13.3 region has more recently been recognized to cause a spectrum of developmental abnormalities including developmental delay, autism, abnormal growth, facial dysmorphism and structural brain abnormalities. Brain abnormalities can involve the corpus callosum, cerebellum, posterior fossa and skull, and may include ventriculomegaly and cerebral atrophy. To our knowledge, this is the first report of polymicrogyria associated with the 17p13.3 contiguous gene duplication syndrome.

The patient is the first child born to healthy, unrelated parents of Portuguese descent with no family history of relevance. There is no antenatal history of maternal illness or exposure to teratogens. Routine 20-week antenatal ultrasound identified mild unilateral cerebral ventriculomegaly and mild bilateral renal pelvis dilatation. Both findings were stable on follow up scans. The baby was born at 39 weeks of gestation via emergency cesarean section due to decreased fetal movements and fetal distress. His Apgar score was 2  at 1 min, 4 at 5 min and 5 at 10 min and he required intubation and ventilation for poor respiratory effort. He was appropriately grown for gestation [birth weight, 3.2 kg (25th centile), length, 51 cm (50th – 75th centile) and head circumference, 35 cm (50th centile)]. He had a metabolic acidosis and severe anaemia of unknown cause (haemoglobin = 50 g/litre). A small retroplacental clot was noted and a Kleihaur test for fetal-maternal haemorrhage was negative. He was transfused with packed red cells, was screened and treated for presumed sepsis and was therapeutically cooled for three days. His recovery was complicated by an episode of presumed sepsis with hypertension on day six. He improved with antimicrobial therapy though all tissue cultures were negative. Additional investigations performed in the neonatal period were a TORCH screen, plasma amino acids and serum ammonia, all of which were normal. Postnatal renal ultrasounds showed resolving left renal pelvis dilatation. He had a normal cardiac ultrasound and normal ophthalmology and audiological assessments. MRI brain scan at 10 days of age showed bilateral perisylvian polymicrogyria (PMG) limited to the posterior perisylvian regions, mild cerebellar hypoplasia involving both vermis and hemispheres, mild dilatation of the lateral ventricles and possible thinning of the corpus callosum (Fig. 1). He had no clinical or electrographic seizures and was discharged home at 21 days. He had mild axial hypotonia in infancy and walked at 18 months. He had delayed speech development and at his most recent assessment at 4 years he was diagnosed with autism spectrum disorder and a mild cognitive disability. He had normal growth, no dysmorphic features and no seizures.

Whole genome SNP microarray analysis was performed using the Illumina HumanCytoSNP-12 BeadChip (approximately 300,000 markers) and Karyostudio software version 1.4 [genome assembly GRCh37/hg19]. This identified a pathogenic gain at position 17p13.3p13.2, 3.9 Mb in size giving the molecular karyotype: arr[hg 19] 17p13.3p13.2 (18901_3978268) ×3 (DECIPHER access number 388737). FISH studies were performed on the proband and both parents. The blood EDTA specimens were prepared using a PHA stimulated culture and, in each case, 15 metaphase cells were examined using the Vysis LSI LIS1 probe and an 18ptel BAC probe. The FISH studies showed this chromosome 17 duplication was translocated distal to the chromosome 18 subtelomeric region with the karyotype 46,XY,ins(18; 17)(pter; p13.3p13.2), and parental FISH studies showed a normal pattern indicating that this is a de novo finding. His microarray was reanalyzed to detect small genomic imbalances of the 18pter region and none were found. The duplicated region of 17p13.3p13.2 in the updated genome assembly GRCh38/hg38 involves 122 genes. 56 of these genes are annotated in OMIM entries, 14 of which are associated with human disease (Table 1). The duplicated region encompasses PAFAH1B1 (LIS1), YWHAE and CRK, all of the genes that have been identified as being potentially contributory to the 17p13.3 contiguous gene duplication syndrome phenotype (Fig. 2). It does not contain any genes known to be associated with PMG.

A custom in-house gene panel that targets 287 genes associated with brain malformations was developed using the HaloPlexHS target enrichment system (Agilent Technology). The target gene list (Supplementary Table 1) includes 35 of 38 genes causative for polymicrogyria/schizencephaly as assessed by the Australian Genomics Health Alliance Brain Malformations Flagship. Fifty nanograms of gDNA was utilized to prepare the sequencing library according to the manufacturer's instructions and 2x150bp paired-end sequencing to a median depth of >600x was performed on a NextSeq (Illumina). The raw data files (fastq.gz) were analysed using both SureCall software (Agilent Technology) and LOVD v.3.0 build 17 software (Leiden University Medical Center).