Contractures of the Hands As a Prenatal Phenotype of <i>CACNA1A</i>‐Related Disorder

What is already known about this topic? Heterozygous variants in CACNA1A are associated with a wide range of variable neurological phenotypes. A prenatal phenotype is not currently recognized for this gene. What does this study add? To our knowledge, this is the first reported case of a prenatal neurological phenotype associated with CACNA1A related disorder in a fetus presenting with clenched hands, bilateral finger contractures, and adducted thumbs. A 40 year old multiparous pregnant woman established antenatal care in her first trimester. She and her partner were non-consanguineous. Maternal history included a previous termination of pregnancy with multiple fetal abnormalities, in whom a molecular diagnosis of trisomy 13 was later confirmed, and a previous healthy male child. Fetal ultrasound scan at 24 weeks gestation in the current pregnancy identified clenched, fist-shaped hands with apparent bilateral finger contractures and adducted thumbs. There was also a thickened nuchal skin fold of 8.5 mm at 24 weeks, and 13 mm at 25 weeks of gestation (see Table 1a). Finger contractures persisted on subsequent antenatal scans. Mild polyhydramnios was observed on later scans in the third trimester. Prenatal QFPCR and microarray on DNA extracted from uncultured amniotic fluid identified an XX (female) chromosome complement with no evidence of any copy number variants of likely clinical significance regarding the scan findings. Antenatal trio exome sequencing and analysis using a fetal anomaly panel were carried out as previously described [1]. This analysis did not detect any variants that could be considered significant with respect to the ultrasound scan findings. Postnatal trio genome sequencing was performed by the Genomics England laboratory pathway and analyzed using a large pediatric disorder panel [2]. The mother had no medical problems and reported normal fetal movements throughout the pregnancy. The neonate was born at 37 weeks of gestation by elective Caesarean section. She had a birthweight of 3.6 kg and was born in good condition. No resuscitation or intensive care admission was required. Bilateral contractures of the third, fourth and fifth digits were noted with adducted thumbs. These improved somewhat with physiotherapy over the first months of life. Clinical Genetics review at 9 months of age noted motor developmental delay, hypotonia and brisk reflexes with a general paucity of movement. Hands were still held with adducted thumbs. The child could roll but was not sitting independently. Dystonic posturing was noted in the limbs. A saccadic eye movement disorder was diagnosed with slightly reduced visual evoked potentials (VEP). Eye structure was normal. MRI of the brain noted benign enlargement of the CSF spaces and no other findings. Creatine kinase and baseline metabolic tests were normal. Postnatal microarray, Prader-Willi methylation testing, DMPK analysis for myotonic dystrophy and Spinal Muscular Atrophy genetic testing were all unremarkable. Postnatal trio genome sequencing identified a de novo heterozygous variant in CACNA1A c.1036_1038del p.(Ile346del) (see Table 1b). Heterozygous variants in CACNA1A are associated with multiple neurodevelopmental phenotypes including developmental and epileptic encephalopathy (#617106), episodic ataxia type 2 (#108500) and migraine, familial hemiplegic with progressive cerebellar ataxia (#141500). The variant was absent from the gnomADv4.1.0 population database (PM2_moderate) and resulted in a protein length change due to an in-frame single amino acid deletion in a non-repeat region (PM4_supporting). The variant was de novo in this patient and was also present in another case from the Genomics England cohort with an overlapping matching phenotype (PS2_strong; PS4_moderate). The variant was therefore classified as likely pathogenic [3]. The postnatal clinical findings were consistent with previously reported cases of CACNA1A-related disorder, including the limb contractures [4]. This case describes an infant with prenatal contractures of both hands, raised nuchal translucency and polyhydramnios, who developed motor delay, hypotonia, dystonia, and a saccadic eye disorder after birth, consistent with a CACNA1A-related disorder. There has been a case report of polyhydramnios identified on antenatal ultrasound in a neonate that would go on to be diagnosed with a CACNA1A disorder after birth [5]. However, no prior evidence could be found for prenatal contractures being associated with CACNA1A variants. This case suggests that prenatal limb contractures is a rare but early detectable manifestation of CACNA1A-related conditions, particularly when identified in conjunction with polyhydramnios. The authors would like to thank the participating family for their help. We thank the Rapid fetal exomes sequencing, specialist NGS team and Bioinformatics team at North Thames Genomic Laboratory Hub for the testing. All research was supported by the NIHR Biomedical Research Center at Great Ormond Street Hospital. The views expressed are those of the author and not necessarily those of the NHS, the NIHR, or the Department of Health and social care. Written parental consent was obtained to share the details of this case. LM has received personal fees for ad hoc consultancy work for Mendelian Ltd, a digital rare disease health company. All other authors have no conflict of interest to declare. The data that supports the findings of this report are available from the authors upon a reasonable request.