European Journal of Medical Genetics 58 (2015) 372e375

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Clinical report

ISPD gene homozygous deletion identified by SNP array confirms prenatal manifestation of WalkereWarburg syndrome Marie Trkova*, Vera Krutilkova, Dagmar Smetanova, Vera Becvarova, Eva Hlavova, Nada Jencikova, Jana Hodacova, Lenka Hnykova, Hana Hroncova, Jiri Horacek, David Stejskal Gennet, Centre for Fetal Medicine, Praha, Czech Republic

a r t i c l e i n f o

a b s t r a c t

Article history: Received 1 December 2014 Accepted 20 May 2015 Available online 16 June 2015

WalkereWarburg syndrome (WWS) is a rare form of autosomal recessive, congenital muscular dystrophy that is associated with brain and eye anomalies. Several genes encoding proteins involved in abnormal adystroglycan glycosylation have been implicated in the aetiology of WWS, most recently the ISPD gene. Typical WWS brain anomalies, such as cobblestone lissencephaly, hydrocephalus and cerebellar malformations, can be prenatally detected through routine ultrasound examinations. Here, we report two karyotypically normal foetuses with multiple brain anomalies that corresponded to WWS symptoms. Using a SNP-array examination on the amniotic fluid DNA, a homozygous microdeletion was identified at 7p21.2p21.1 within the ISPD gene. Published data and our findings led us to the conclusion that a homozygous segmental intragenic deletion of the ISPD gene causes the most severe phenotype of WalkereWarburg syndrome. Our results also clearly supports the use of chromosomal microarray analysis as a first-line diagnostic test in patients with a foetus with one or more major structural abnormalities identified on ultrasonographic examination. Ó 2015 Elsevier Masson SAS. All rights reserved.

Keywords: WalkereWarburg syndrome ISPD gene Brain anomalies SNP array 7p21 microdeletion

1. Introduction WalkereWarburg syndrome (WWS) is an autosomal recessive, multisystem disorder characterised by major neurological deficits, visual and muscular impairments, and a rapidly fatal outcome [Dobyns et al., 1989]. Classically, syndromes with cerebral ocular, and muscular dystrophy were attributed to aberrant adystroglycan glycosylation [Roscioli et al., 2012]. a-dystroglycan and b-dystroglycan are central components of the dystrophinglycoprotein complex, which forms a link between the cytoskeleton and the basal lamina [Buysse et al., 2013]. Mutations in 18 genes encoding putative or confirmed glycosyltransferases or other proteins involved in the a-dystroglycan glycosylation pathway have been identified in the dystroglycanopathies: POMT1, POMT2, POMGNT1, FKTN, FKRP, LARGE, ISPD, GTDC2 (POMGT2), DAG1, TMEM5, B3GALNT2, SGK196 (POMK), B3GNT1 (B4GAT1), GMPPB, DOLK, DPM1, DPM2 and DPM3, as reviewed by

* Corresponding author. Gennet, Centre for Fetal Medicine, Kostelní 9, 170 00, Praha 7, Czech Republic. Tel.: þ420 242456736; fax: þ420 242456722. E-mail address: [email protected] (M. Trkova). http://dx.doi.org/10.1016/j.ejmg.2015.05.004 1769-7212/Ó 2015 Elsevier Masson SAS. All rights reserved.

[Ohtsuka et al., 2015]. Recently, bi-allelic loss-of function mutations in the isoprenoid synthase domain-containing gene (ISPD, OMIM614631), which maps to chromosome 7p21, were identified as a second most common cause of WWS [Roscioli et al., 2012; Willer et al., 2012]. While the WWS phenotype of the affected individuals with ISPD mutations was described for postnatal cases [Cirak et al., 2013; Czeschik et al., 2013; Roscioli et al., 2012; Willer et al., 2012], only few prenatal cases were published [Vuillaumier-Barrot et al., 2012]. We report two prenatally detected ISPD gene deletions in foetuses with multiple brain anomalies that corresponded to the WWS phenotype. 2. Clinical report A 22-year-old woman underwent a second trimester screening at our clinic during her third gravidity. With the same partner, a 22year-old healthy male, she had a 4-year-old healthy daughter and a history of one miscarriage during the first trimester (3 years before this gravidity). The woman was referred for amniotic fluid sampling because of positive biochemical screening (increased alphafetoprotein, neural tube defect risk 1:2) on the 15th week of

M. Trkova et al. / European Journal of Medical Genetics 58 (2015) 372e375

gestation (WG). Ultrasound examination during the 17th WG showed intrauterine growth restriction and gastroschisis (Foetus 1/ F1) (Fig. 1a). Karyotyping and array examination were performed. A later ultrasound on the 21st WG confirmed a 24  35  19 mm gastroschisis formed by the small intestine. The woman continued the pregnancy, and the daughter was born at 37 weeks of gestation with weight 2400 g. She underwent successful surgery for the gastroschisis immediately after her delivery: reposition of the small intestine and the stomach into abdominal cavity and suture of the abdominal wall. On 6th day the enteral intake was started and progressive per oral nutrition was successively tolerated. The girl was dismissed from the hospital on 33rd day after surgery with weight 2888 g. Sonography of the brain did not reveal any abnormalities. 11 months later, ultrasound examination in the 20th WG of her fourth gravidity with normal biochemical screening (Foetus 2/F2) showed a 12  10 mm occipital meningocele, hydrocephalus, obliteration of the cisterna magna (banana sign), corpus callosum agenesis, dilated III cerebral ventricle, and a multicystic left kidney (Fig. 1bed). Amniotic fluid sampling, followed by karyotyping and array examination, was performed. Clinical features and laboratory results (including SNP array data) were discussed with the couple, and the parents decided to terminate pregnancy during the 21st WG. The autopsy confirmed female foetus with weight of 350 g and length 170 mm, occipital subcutaneous protrusion with 15 mm diameter, absent brain gyrification, enlarged lateral ventricles, corpus callosum agenesis and multicystic dysplasia of the left kidney. 6 months later, the woman underwent a second trimester ultrasound examination in the 17th WG of her fifth gravidity (Foetus 3/F3). The findings included hydrocephalus, cerebellar vermis agenesis, and a dilated IV cerebral ventricle (Fig. 1eef). Amniotic fluid sampling for array was performed. The poor prognosis of the brain structural anomalies together with SNP array data were discussed with the couple, and the pregnancy was terminated

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during the 18th WG. Unfortunately, the autopsy report is not available. In addition to the classic karyotype, SNP array examination (whole genome genotyping of 298,649 SNPs) was performed on the DNA isolated from the amniotic fluid samples of foetuses F1, F2, F3 and on the DNA isolated from the lymphoblastoid cell line of both parents; the genotyping analysis was performed using the Illumina HumanCytoSNP-12v2.1 platform (Illumina, Inc., San Diego, CA). All the data were analysed using the GenomeStudio v2011.1 software. RefSeq genes and base positions were annotated according to the UCSC Human genome assembly GRCh37/hg19. Karyotypes of the three foetuses F1, F2, and F3 were normal (F1/ 46, XX; F2/46, XX, and F3/46, XY). SNP array analysis of all of the samples, including the parents and the three foetuses, revealed a total of 12 copy number variations (CNVs). The summary of all of the CNVs, their clinical interpretation and their parental origin are shown in Table 1. Taking into account the similar ultrasound findings for F2 and F3, we searched for an identical abnormality. We found a 360 kb long homozygous microdeletion at 7p21.2p21.1 that spanned 9 out of the 10 exons of the ISPD gene (isoprenoid synthase domain-containing protein, OMIM 614631). Recessive mutations in the ISPD gene were recently identified in individuals with WalkereWarburg syndrome [Roscioli et al., 2012; Willer et al., 2012]. The multiple brain ultrasound anomalies were consistent with the postnatal phenotype of WWS, and the homozygous 7p21.2p21.1 microdeletion was considered pathogenic. The mother, father and foetus F1/girl with gastroschisis carried the same heterozygous microdeletion. 4. Discussion Brain anomalies are among the most prevalent sonographic indications for second trimester prenatal microarray analysis for foetuses with normal karyotypes; 12% of the sonographic anomalies observed in the Kleeman study were brain anomalies [Kleeman

Fig. 1. Ultrasound findings in three foetuses of one family. (Ultrasound anomalies are indicated by the white arrows). a: gastroschisis formed by the small intestine in foetus 1 (F1). b: multicystic left kidney in foetus 2 (F2). c: ventriculomegaly in foetus 2 (F2). d: occipital meningocele in foetus 2 (F2). e: cerebellar vermis agenesis, dilated IV cerebral ventricle in foetus 3 (F3), f e ventriculomegaly in foetus 3 (F3).

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Table 1 The summary of all CNVs in five individuals of one family: 3 foetuses (F1, F2, F3) with ultrasound findings and healthy mother and father. The table includes CNVs positions, clinical interpretation and parental origin of the CNVs. 360 kb heterozygous or homozygous microdeletion 7p21.2p21.1span the ISPD gene. Sample Diagnosis

CNV

Clinical interpretation

F1

arr[hg19] 7p21.2p21.1(16,137,43616,500,884)x1 mat arr[hg19] 8q24.23(137,730,280137,850,011)x1 pat arr[hg19] 7p21.2p21.1(16,137,43616,500,884)x0 mat pat arr[hg19] 8q24.23(137,730,280137,850,011)x1 mat arr[hg19] 7p21.2p21.1(16,137,43616,500,884)x0 mat pat arr[hg19] 20p12.1(14,517,22014,579,703)x1 mat arr[hg19] 7p21.2p21.1(16,137,43616,500,884)x1 arr[hg19] 8q21.3(88,414,58188,549,744)x3 arr[hg19] 8q24.23(137,730,280137,850,011)x1 arr[hg19] 20p12.1(14,517,22014,579,703)x1 arr[hg19] 7p21.2p21.1(16,137,43616,500,884)x1 arr[hg19] 8q24.23(137,730,280137,850,011)x1

Heterozygous carrier

F2

F3

IUGR, gastroschisis

Multiple brain anomalies

Multiple brain anomalies

Mother Healthy

Father

Healthy

Most likely benign Clinically relevant Most likely benign Clinically relevant Most likely benign Heterozygous carrier Most likely benign Most likely benign Most likely benign Heterozygous carrier Most likely benign

CNV e copy number variation; IUGR e intrauterine growth restriction; mat e maternal origin; pat e paternal origin.

et al., 2009], and the same was true for the Gennet study (unpublished data). There are a large number of OMIM syndromes and diseases that can be associated with brain anomalies. The phenotypic signs of both karyotypically normal foetuses F2 and F3 matched to symptoms of 46 and 57 Orphanet syndromes, including WalkereWarburg syndrome, respectively. Array examination of the amniotic fluid samples of both foetuses F2 and F3 revealed an identical homozygous microdeletion at 7p21.2p21.1, and subsequent parental peripheral blood examinations confirmed heterozygous 7p21.2p21.1 microdeletions in both partners. The microdeletion affected almost the whole ISPD gene (9 out of 10 exons). Recent studies using fibroblast complementation assay, linkage analysis and targeted sequencing identified autosomal recessive mutations in the ISPD gene in patients with WalkereWarburg syndrome [Roscioli et al., 2012; Willer et al., 2012]. WalkereWarburg syndrome is an autosomal, recessive, multisystem disorder that is characterised by aberrant a-dystroglycan glycosylation. Glycosylated dystroglycan plays a key role as a determinant of axon guidance cue distribution and function in the mammalian nervous system [Wright et al., 2012]. The mechanism by which ISPD gene mutations lead to a reduction of a-dystroglycan glycosylation is not well understood; however, the pivotal role of ISPD in the initial step of Omannosylation of -a-dystroglycan was recently described. Omannosylation is an important step in glycosylation and is essential for the interaction of a-dystroglycan with extracellular matrix proteins, such as laminin-a2 [Cirak et al., 2013]. Six

studies of the ISPD gene mutations in patients with cobblestone lissencephaly [Vuillaumier-Barrot et al., 2012], WWS [Czeschik et al., 2013; Roscioli et al., 2012; Willer et al., 2012] and congenital and limb-girdle muscular dystrophies [Baranello et al., 2015; Cirak et al., 2013] have been published, and multiple rare variants were found in 29 independent families. All affected individuals with homozygous segmental intragenic deletion of the ISPD gene exhibited progressive muscular dystrophy with a severe WWS phenotype, including hydrocephalus, cobblestone lissencephaly of the cerebral cortex, severe brainstem hypoplasia and hypoplasia of the cerebellum cases [Roscioli et al., 2012; Willer et al., 2012]. The microdeletion spanning the ISPD gene is very rare CNV in the healthy population. The search in the DGV database (http://projects.tcag.ca/variation) did not reveal any similar microdeletion and we did not find the same CNV in our internal Czech database of CNVs, which contains a total of 1633 samples (unpublished data). To detect possible parental consanguinity, the absence of heterozygosity (AOH) (uninterrupted homozygote blocs  3 Mb) [Fan et al., 2013] was calculated in all foetuses. Nevertheless, 1e2% of the AOH in foetuses F1, F2 and F3 did not suggest the likelihood of a direct biological relationship between the parents. However, the family belongs to the Czech Roma population, and individuals from these populations could share a common ancestor. It would be interesting to examine if there is an increased incidence of WWS in this population, which could be consistent with the deletion being introduced by a common ancestor. Unfortunately, we have not had a chance to perform microdeletion testing in the broader families of both parents to prove this. The risk of WalkereWarburg syndrome in the repeated pregnancies correlates with the common risk of an autosomal recessive disease, and prenatal testing of the next pregnancy is highly recommended. Preimplantation genetic diagnosis could be discussed with the parents. The 7p21.2p21.1 microdeletion was 360 kb in size and invisible using routine cytogenetic examination. This result is in concordance with the previously published data on the importance of chromosomal microarray technique in prenatal diagnosis [Faas et al., 2012]. It also clearly supports the current recommendation of ACOG (American College of Obstetricians and Gynecologists) for the use of chromosomal microarray analysis as a first trial test in patients with a foetus with one or more major structural abnormalities identified on ultrasonographic examination [Committee Opinion No 581, 2013]. Our data show that high array resolution is desirable as array with resolution of >500 kb would have missed this particular deletion. Conflict of interest The authors declare no conflict of interest. References Baranello G, Saredi S, Sansanelli S, Savadori P, Canioni E, Chiapparini L, et al. A novel homozygous ISPD gene mutation causing phenotype variability in a consanguineous family. Neuromuscul Disord 2015;25:55e9. Buysse K, Riemersma M, Powell G, van Reeuwijk J, Chitayat D, Rosciol T, et al. Missense mutations in b-1,3-N-acetylglucosaminyltransferase 1 (B3GNT1) cause WalkereWarburg syndrome. Hum Mol Genet 2013;22:1746e54. Cirak S, Foley AR, Herrmann R, Willer T, Yau S, Stevens E, et al. ISPD gene mutations are a common cause of congenital and limb-girdle muscular dystrophies. Brain 2013;136:269e81. Committee Opinion No 581. The use of chromosomal microarray analysis in prenatal diagnosis. Obstet Gynecol 2013;122:1374e7. Czeschik JC, Hehr U, Hartmann B, Lüdecke HJ, Rosenbaum T, Schweiger B, et al. 160 kb deletion in ISPD unmasking a recessive mutation in a patient with Walkere Warburg syndrome. Eur J Med Genet 2013;56:689e94. Dobyns WB, Pagon RA, Armstrong D, Curry CJ, Greenberg F, Grix A, et al. Diagnostic criteria for WalkereWarburg syndrome. Am J Med Genet 1989;32:195e210.

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ISPD gene homozygous deletion identified by SNP array confirms prenatal manifestation of Walker-Warburg syndrome.

Walker-Warburg syndrome (WWS) is a rare form of autosomal recessive, congenital muscular dystrophy that is associated with brain and eye anomalies. Se...
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