A novel SMOC1 pathogenic homozygous variant in a fetus with mesomelia of the lower limbs, micrognathia and hypertelorism and an incidental finding of CYP21A2‐related congenital adrenal hyperplasia

Trio exome sequencing was performed on a fetus with bilateral mesomelia of the lower limbs with significant angulation of the tibial bones, micrognathia and hypertelorism detected on ultrasound scan at 19 + 0 weeks gestation. The couple is consanguineous. A homozygous pathogenic frameshift variant in the SMOC1 gene (c.339_340del p.(Phe114Cysfs*40)) was detected and both parents were shown to be heterozygous. Pathogenic variants in the SMOC1 gene are associated with microphthalmia with limb anomalies which multidisciplinary team discussion determined to be causal of the scan anomalies detected. The fetus was also a compound heterozygote for CYP21A2 pathogenic variants, confirming a second diagnosis of non‐classical congenital adrenal hyperplasia, which was felt incidental to the scan findings. The risk that this couple's next pregnancy would be affected by either of these disorders is 1 in 4 (25%) and demonstrates the importance of genetic diagnoses for the family and implications for future pregnancies.


| REPORT 1.| Fetal phenotype
Ultrasound scan at 19 þ 0 weeks gestation showed lower limb mesomelia, abnormal right tibia and fibula and severe bowing of left lower limbs (Figure 1).Facial views suggested micrognathia and hypertelorism and the eyes appeared small.Both kidneys appeared present although the right kidney was more difficult to visualize.
No anomalies were detected by fetal echo.The parents are consanguineous.

| Diagnostic method
Fetal DNA was extracted from amniocytes and genomic DNA was extracted from parental blood samples.Trio exome sequencing and analysis using the fetal anomalies panel 1 was carried out as previously described. 2QF-PCR for common aneuploidies and microarray analysis showed a female chromosome complement with no pathogenic copy number variants.

| Diagnostic results and interpretation
Trio exome analysis identified a novel homozygous pathogenic frameshift variant in the SMOC1 gene with biparental inheritance (Table 1).Biallelic pathogenic variants in SMOC1 are associated with microphthalmia with limb anomalies (MIM 206920) and prenatal presentations have been reported previously, with features including depression of the frontal bone, posterior fossa anomalies, cerebral ventricular enlargement, clefting of the sacral and lower-lumbar vertebrae, and bilateral microphthalmia identified sonographically, with micrognathia, oligodactyly and tibial bowing identified after fetal autopsy. 3The SMOC1 frameshift variant identified in this study is predicted to undergo nonsense-medicated decay causing loss of function, which is a known disease mechanism.This variant was also absent from the gnomAD population database, resulting in a pathogenic variant classification.To the best of our knowledge, this variant has not previously been reported in the literature or variant databases.SMOC1 is essential for ocular and limb development in both humans and mice. 4Multidisciplinary team discussions determined that this variant is likely to fully explain the imaging findings; angulated tibia suggesting limb anomalies and hypertelorism with underdeveloped globes, which could reflect microphthalmia.
In addition, the fetus was found to be a compound heterozygote for two previously published CYP21A2 pathogenic variants (Table 2) that are associated with the non-classical form of congenital adrenal hyperplasia (CAH) 5 that does not present prenatally.Because of the presence of the pseudogene, long-range PCR testing was utilized to confirm that both variants were present in the real gene.This was therefore deemed to be an incidental finding which agreed to be of clinical significance following multidisciplinary team discussions and reported.
Both genetic findings had implications for future offspring and provided the option of prenatal testing and carrier testing for appropriate family members following genetic counseling.

| Pregnancy outcome
The parents were committed to the pregnancy and a further scan at 24 þ 0 weeks showed bilateral severe micro/anophthalmia, mild micrognathia, cross-fused left kidney and lower limb shortening and bowing.Parents were offered counseling and continued ultrasound surveillance; a fetal brain MRI at a later gestation was recommended; however, the pregnancy ended with fetal demise.After birth, external examination confirmed significant issues with shortening and bowing of the left leg and possibly a missing toe, and the eyes could not be visualised.The parents declined full post-mortem.

| Discussion
The future offspring of this couple are at 1 in 4 risk of being affected by SMOC1-related disorder or CYP21A2-related CAH and 1 in 16 risk of being affected by both conditions.Following genetic counseling, the couple opted for invasive prenatal testing in their next pregnancy, in which the fetus was an unaffected carrier of both conditions.This case provides additional information on the prenatal phenotype for SMOC1-related disorders with features in common with the prenatal phenotype previously reported. 3The additional scan findings seen at 24 þ 0 weeks were consistent with the diagnosis as bilateral severe micro/anophthalmia and limb anomalies were detected.The cross-fused left kidney seen in this case has not specifically been reported in affected individuals, although horseshoe kidneys have been seen on imaging in 4/8 probands with biallelic SMOC1 variants. 6This is considered a similar anomaly to the cross-fused kidney seen in this case and is T A B L E 2 Genetic findings.for this condition in 25 families. 6This case also highlights that any type of biallelic variant can be seen in consanguineous couples and the importance of considering all inheritance patterns when analysing trio exome data.It also demonstrates how exome sequencing can reveal unexpected findings which may not be related to the scan features but can have other health implications for the baby and future pregnancies.

F I G U R E 1
Scan images showing (A) short, nagulated right tibia; (B) short bowed left tibia and fibula; (C) small orbits and (D) micrognathia.[Colour figure can be viewed at wileyonlinelibrary.com] 165.1 cm and father 167.6 cm, limbs proportional with no deformities and no history of fractures.Pregnancy loss-fetal Doppler changes were seen on the ultrasound in the preceding week prior to demise and patient was seen a week later with reduced fetal movements and an intra-uterine demise diagnosed at 25 þ 1 with SMOC1-related disorders.In keeping with a significant genetic diagnosis associated with structural anomalies, the patient was counseled about increased risks of in-utero demise.The anomalies themselves do not directly explain the demise but this outcome was clearly a possibility in this context and perinatal or early postnatal death has been previously reported (10/35 cases) consistent