A novel frameshift deletion variant of ARSL associated with X-linked recessive chondrodysplasia punctata 1: a case report and literature review of prenatal, confirmed cases | BMC Medical Genomics

Chondrodysplasia punctata (CDP) is a heterogeneous group of skeletal dysplasia with characteristic radiographic stippling in multiple epiphyses. CDP contains rhizomelic chondrodysplasia punctata (RCDP, a peroxisome biogenesis disorder), X-linked dominant CDP (CDPX2, also known as Conradi-Hnermann syndrome OMIM #302960, impaired cholesterol biosynthesis), brachytelephalangic chondrodysplasia punctata (BCDP) / X-linked chondrodysplasia punctata 1 (CDPX1), and other disorders resulting from chromosomal abnormalities, maternal autoimmune diseases, use of warfarin during pregnancy, or maternal alcohol consumption [10]. Though there is partial overlap in ultrasound features, distinct causative genes are known to underlie different types of CDP, highlighting a diagnostic value of genetic testing in prenatal cases. In this study, the ultrasound findings at 24 weeks of gestation were insufficient to establish a definitive diagnosis. Identification of the ARSL c.1108del variant led to a final diagnosis of CDPX1.

A review of prenatal cases of CDPX1 with a molecular diagnosis published in literature and this study gives implications for perinatal management of this condition (Table 1). Of the 10 cases reviewed, prenatal ultrasound (MRI/CT) scan detected midface hypoplasia to various degrees in eight cases (80%), epiphyseal stippling in four cases (40%), brachytelephalangy in two cases (20%), with two cases (20%) presenting with all the three features concurrently. Other structural ultrasound anomalies that were recurrently detected include spine abnormality (5/10, 50%) and short limbs (4/10, 40%). The mutation spectrum of the cases includes one frameshift, one nonsense, two deletion (partial or contiguous), and six missense mutations. However, no clear genotype-phenotype correlation has been established [7]. Because of the variability of clinical manifestation, prenatal counseling of the condition is quite challenging [11]. One individual harboring a partial deletion of the ARSL gene had severe respiratory distress, which resulted in neonatal death on day 2 after birth [12], whereas another individual carrying a contiguous deletion on Xp22.33 region that affects multiple genes including ARSL displayed mild respiratory problem and survived postnatally [13] (Table 1). Of note, the 8.33 Mb contiguous deletion involving other genes (SHOX, CSF2RA, XG, NLGN4 and STS) along with the ARSL gene caused additional clinical manifestations, such as X-linked ichthyosis associated with a deletion of the STS gene [13]. Furthermore, another previous study has described a contiguous gene syndrome in two brothers from a Moroccan family who had short stature, hypertelorism, midface hypoplasia, sensorineural hearing loss, brachytelephalangy, and normal intelligence. The probands were carriers of a maternally inherited 3.1-Mb deletion on Xp22.33 covering the short stature homeobox (SHOX) and ARSL genes [14]. Therefore, both previous and present studies remind clinicians that a comprehensive postnatal examination is necessary for the newborns with CDPX1 to detect other malformations and complications for receiving timely medical care.

ARSL encodes an acrylsulfatase that is localized to the Golgi apparatus membrane [15]. Reportedly, 60-75% of patients with CDPX1 carried ARSL point mutations; and Xp22.3 deletion or chromosomal rearrangement accounted for the further 25% of patients [16]. Therefore, a sequential karyotyping, CNV-seq and exome sequencing strategy is recommended for prenatal diagnosis of CDPX1. In this study, following a finding of normal karyotype and a negative result of CNV-seq, exomse sequencing identified a single nucleotide frameshift deletion variant of ARSL as the underlying genetic cause for the fetal anomalies. To date, the identified ARSL point mutations are predominantly missense mutations, whereas frameshift and nonsense mutations are relatively infrequent. This study provides useful information on the clinical phenotype of the ARSL c.1108del variant. Because of the developmental stage, the clinical presentation of the c.1108del variant may not be fully evocative in the fetus. Thus, it is difficult to evaluate the prognosis of this variant in the study.

In conclusion, a novel frameshift deletion variant of ARSL and the associated fetal phenotype have been identified. This study provides useful information for prenatal diagnosis and genetic counseling.