Introduction: Alkuraya-Kučinskas syndrome is a rare autosomal recessive disorder characterized by multiple anomalies, including polyhydramnios, arthrogryposis, clenched hands, clubbed feet, brain abnormalities associated with cerebral parenchymal underdevelopment, dysmorphic facial features, and renal involvement. This disease was first characterized and named in 2018, and biallelic pathogenic variants in the KIAA1109 gene were determined to be the cause of this severe disease. At our institution, trio testing was ordered on a male newborn with overlapping features. Methods: Genomic DNA extracted from submitted specimens from the proband and both parents was enriched for coding and adjacent non-coding regions by hybridization-capture using IDT xGen Exome Research Panel v2 (Integrated DNA Technologies, Coralville, IA). Library products were sequenced on the Illumina NovaSeq. After alignment to the reference genome (UCSC hg19), variants were detected using several different variant calling algorithms. Sequence alterations were described according to Human Genome Variation Society (HGVS) nomenclature guidelines and were classified according to variant interpretation guidelines of the American College of Medical Genetics and Genomics (ACMG). Results: Trio whole-exome sequencing identified compound heterozygous pathogenic variants in the KIAA1109 gene. The first variant (c.6398_6402delinsCAAAGTTACC [p.Leu2133Serfs*6]) is a paternally inherited deletion-insertion variant. This alteration is predicted to shift the reading frame with substitution of leucine by serine at amino acid position 2133 followed by introduction of a premature stop codon. The second variant (c.12272_12273dup [p.Pro4092Ilefs*32]) is a maternally inherited 2-bp duplication. This alteration is predicted to shift the reading frame with substitution of proline by isoleucine at amino acid position 4092 followed by introduction of a premature stop codon. Both variants are predicted to result in loss of KIAA1109 function due to premature protein truncation and/or nonsense-mediated mRNA decay. Both variants were classified as pathogenic per ACMG guidelines and were confirmed by Sanger sequencing. Conclusions: Here we report compound heterozygous frameshifting variants in the KIAA1109 gene, which were revealed by trio testing to be inherited from reportedly unrelated parents, that resulted in early death of the proband due to Alkuraya-Kučinskas syndrome. In the literature, similar truncating KIAA1109 variants in both the homozygous and compound heterozygous state have been reported in cases of early death, whereas missense variants have been reported in milder disease cases with occasional survival. To our knowledge, this represents the second reported case of Alkuraya�Kučinskas in the United States.