P493: Deletions of the 19q13.11 region involving SCN1B are risk factors for febrile seizures

Conclusion:As the understanding of the phenotypic spectrum of COASY-related disorders evolves, this case highlights the importance of documenting novel variant combinations to better understand genotype-phenotype relationships, ultimately improving diagnosis, patient care, prognostication, and family counseling.Introduction: COASY (HGNC:29932) encodes the bifunctional protein coenzyme A synthase which catalyzes the final steps of CoA synthesis.Biallelic pathogenic COASY variants are linked to COASY-protein associated neurodegeneration (CoPAN) [OMIM#615643] and pontocerebellar hypoplasia type 12 (PCH12) [OMIM#618266].Recent reports have described new and unique clinical findings, suggesting that COASY-related disorders represent a continuum between CoPAN and PCH12 phenotypes.Case Presentation: A 2-week-old female of El Salvadorian descent was prenatally identified with bilateral talipes equinovarus, severe microcephaly (3 standard deviations below the mean), cerebellum less than the 1 st percentile below the vermis, hands clenched concerning for arthrogryposis, mild polyhydramnios, and scalp edema.Fetal MRI at 32 weeks confirmed severe microcephaly with almost all intracranial measurements less than the 3rd percentile for gestational age, flat appearing belly of pons, and thin appearing brainstem.The patient was delivered at 38 weeks gestation via C-section for fetal distress, birth weight was 2.39 kg, birth length 42.55 cm, head circumference 29 cm, with Apgar scores of 3 and 8 at 1 and 5 minutes.She had respiratory failure at birth and tonic/clonic movements at 5 minutes of life concerning for seizure.Exam findings included diffuse hypotonia, decreased muscle bulk, arthrogryposis (bent elbows/knees, clubfeet, overlapping fingers), thick hair with a low anterior hairline, and microcephaly.Postnatal MRI confirmed simplified gyral pattern, cerebellar and brainstem hypoplasia, diffuse white matter hypoplasia, and globular appearance of the basal ganglia with an absent anterior limb of the internal capsule.Diagnostic Workup: Exome sequencing revealed compound heterozygous COASY variants: maternally inherited c.641C>T (p.Ala214Val) and paternally inherited c.1015C>T (p.Arg339*) (reference sequence: NM_025233.7).The missense c.641C>T, p.Ala214Val) variant, found in 4/1,610,184 alleles without homozygotes in gnomAD (v4.1.0),in-silico predictions suggest a deleterious effect on the protein structure or function, has been reported previously in the compound heterozygous state with another missense variant (c.1495C > T, p.Arg499Cys) in 2 siblings of Turkish descent with COASY-related CoPAN.Their clinical features included intellectual disability, early onset ataxia, spastic paraparesis, pyramidal signs, and behavior abnormalities, as well as mild microcephaly and short stature.The nonsense c.1015C>T, (p.Arg339*) variant, present in 23/1,613,466 alleles without homozygotes in gnomAD (v4.1.0),is not previously reported but is predicted to result in an absent or abnormal truncated COASY protein.Loss-of-function variants in COASY are known to be pathogenic.