P453: PTEN and WDR19 variants in a neonate with brain and cutaneous anomalies

Outcome and Follow-Up: At the age of 14-month, he is growing and developing on track.He has been noted to have constipation requiring maintenance medication and is also undergoing workup for any pulmonary contributions to his pulmonary hypertension.Discussion: Literature review uncovered catalogued surviving hemizygous males with similar features.Our patient's variant resides upstream of actin-binding domain and separated from other defined domains of filamin A; his phenotype overlaps with males with other missense variants in proximity: CVD and PVNH with or without connective tissue involvement.Interestingly, these cases with PVNH resemble FLNA-related PVNH 1 (OMIM 300049), which classically affects females with heterozygous truncating variants and causes male lethality.Furthermore, our patient's constipation could potentially have a similar mechanism to congenital idiopathic intestinal pseudoobstruction (OMIM 300048).Additionally, FLNA has been implicated in interstitial lung disease, for which our patient is undergoing evaluation.To further investigate the FLNA-related phenotypic landscape, we found 6 (4 surviving) other males with likely pathogenic variants in FLNA from our institution since 2016, many with novel variants but none with significant phenotypic overlap with our patient.There are 2 with X-linked CVD (with one deceased at 4 months of age due to cardiac complications), 2 with otopalatodigital spectrum (one with severe skeletal dysplasia along with multi-systemic manifestations deceased at 4 months of age from airway complications), one (c.5254C>T; p.Q1752X) with primarily periventricular nodular heterotopia and one (c.6478+1G>T;IVS39+1G>T, detailed in a previous publication) with predominantly renal/genitourinary phenotype.These cases confirm most but not all variant-to-phenotype approximations described in literature.Furthermore, these 7 male cases contrasted with 7 (6 surviving) female cases from the same time frame, potentially suggesting female underdiagnoses. Conclusion:The phenotypic landscape of FLNA hemizygous males has been broadened by the cases highlighted here, including a mildly affected infant, which could infuse cautious optimism to their prognostication.This process is also facilitated by certain variants' adherence to predicted phenotype approximations.Still, unexpected phenotypic manifestations of other variants remain yet to be elucidated.Introduction: The advent and advancement of genetic sequencing technology has expanded the phenotypic spectrum of FLNA (OMIM 300017), challenging the historical notion that hemizygous males face guarded prognoses.This in turn complicates the process of providing anticipatory counseling or commenting on the candidacy for risky/invasive medical interventions for affected young males.We present our experience with diagnosis, counseling and medical decision making on a male case of Filamin A deficiency with novel variant, then review other surviving male patients from our institution.Case Presentation: The diagnosis was made prenatally due to ultrasound findings of polyvalular cardiac disease, unilateral talipes equinovarus and mega cisterna magna.Diagnostic Workup: Molecular testing revealed 'de novo' variant c.124A>G (p.K42E) in FLNA.The prenatal counseling at the time reviewed the 9 defined FLNA-related syndromes and focused on X-linked cardiac valvular dysplasia (CVD) (OMIM 314400), whose prognosis is contingent on primarily its cardiac manifestation, and Melnick-Needles syndrome (OMIM 309350), the most severe skeletal dysplasia on the otopalatodigital spectrum conferring grim prognoses independent of sex.