Loading HPO index and embeddings... Starting HPO search... Searching for: elevated branched-chain amino acids Searching for: poor feeding Searching for: repeated emesis Searching for: lethargy Searching for: tachypnea Searching for: sweet burnt-sugar odor urine HPO search completed. Found terms: HP:0008344: Elevated circulating branched chain amino acid concentration (Reasoning: This term was selected because newborn screening showed markedly elevated branched-chain amino acids in the blood, and this was the top-matching, clinically precise term referring to blood levels.) HP:0008872: Feeding difficulties in infancy (Reasoning: Poor feeding was described on day 4 of life. This term is clinically appropriate as it specifies feeding difficulty in infancy with the highest similarity score among infant-specific terms.) HP:0001254: Lethargy (Reasoning: By day 5 the infant was described as lethargic, and this matches the term 'Lethargy' directly, with a high similarity score and clinical specificity.) HP:0033072: Abnormal macroscopic urine appearance (Reasoning: A 'sweet, burnt-sugar' odor in the diapers was noted, which is reflected by this term's inclusion of abnormal urine odor.) Starting gene search... Finding genes for HPO terms: HP:0008344, HP:0008872, HP:0001254, HP:0033072 Gene search completed. Ranked genes: Gene: BCKDHA, Rank: 1, Reasoning: BCKDHA is associated with three of the submitted HPO terms: elevated circulating branched chain amino acid concentration (HP:0008344), feeding difficulties in infancy (HP:0008872), and lethargy (HP:0001254). Importantly, BCKDHA mutations cause Maple Syrup Urine Disease (MSUD), which is strongly associated with all the above features and the classic abnormal urine odor. The gene directly fits the clinical scenario of abnormal branched-chain amino acids, lethargy, feeding problems, and typically abnormal urine. Gene: CPT2, Rank: 2, Reasoning: CPT2 is associated with lethargy (HP:0001254), abnormal macroscopic urine appearance (HP:0033072), and feeding difficulties in infancy (HP:0008872). While CPT2 deficiency can present with lethargy and feeding issues, abnormal branched chain amino acids are not characteristic for CPT2. The gene is included due to HPO matches, but does not explain the key metabolic laboratory finding as well as BCKDHA. Gene: KCNA1, Rank: 3, Reasoning: KCNA1 is linked to feeding difficulties (HP:0008872) and lethargy (HP:0001254). However, it is not associated with abnormal branched chain amino acids or abnormal urine appearance, making it less likely given the submitted clinical scenario. Gene: PLCH1, Rank: 4, Reasoning: PLCH1 is associated with feeding difficulties and lethargy but not with branched chain aminoacidemia or abnormal urine appearance. Less likely than genes affecting metabolism directly. Gene: GATA1, Rank: 5, Reasoning: GATA1 is matched to lethargy and abnormal urine, without a direct correlation with branched chain amino acids or classic metabolic presentations such as MSUD. Gene: PNKP, Rank: 6, Reasoning: PNKP connects with feeding difficulties and lethargy but does not fit the specific biochemical abnormality found in the case. No link to branched chain amino acids. Gene: STIL, Rank: 7, Reasoning: STIL has association with lethargy and feeding difficulties but no known link to branched chain amino acid abnormalities or abnormal urine. Gene: STAG2, Rank: 8, Reasoning: STAG2 is linked to feeding difficulties and lethargy, but is not implicated in disorders of amino acid metabolism, so is lower priority. Gene: POU1F1, Rank: 9, Reasoning: POU1F1 is associated with feeding difficulties and lethargy but not with branched chain amino acids. Not consistent with the metabolic abnormality described. Gene: NDUFS8, Rank: 10, Reasoning: NDUFS8 is associated with lethargy and feeding issues, but not elevated branched chain amino acids or abnormal urine; not a primary candidate for the described clinical picture. Gene: LHX3, Rank: 11, Reasoning: LHX3 is tied to feeding issues and lethargy, not with branched chain amino acids or abnormal urine, making it unlikely in this scenario. Gene: IVD, Rank: 12, Reasoning: IVD is associated with feeding difficulties and lethargy. Although IVD is related to isovaleric acidemia (causing a sweaty/burnt odor in urine), it is not a primary cause of elevated branched chain amino acids as in MSUD. Gene: PRDX1, Rank: 13, Reasoning: PRDX1 associates with feeding problems and lethargy but does not match metabolic findings. Gene: PROP1, Rank: 14, Reasoning: PROP1 is tied to feeding and lethargy but has no clear metabolic correlation with the findings here. Gene: CRIPTO, Rank: 15, Reasoning: CRIPTO connects with feeding and lethargy, not amino acid metabolism or specific metabolic odor. Gene: SMC1A, Rank: 16, Reasoning: SMC1A is associated with feeding and lethargy, but not with branched-chain amino acids or abnormal urine. Gene: PTCH1, Rank: 17, Reasoning: PTCH1 is associated with feeding and lethargy but not metabolic complications as in this clinical context. Gene: IYD, Rank: 18, Reasoning: IYD is linked with feeding difficulties and lethargy, yet does not fit the specific findings suggestive of MSUD or similar disorders. Gene: LHX4, Rank: 19, Reasoning: LHX4 is tied to feeding and lethargy, no link with branched-chain amino acid disorders. Gene: CDON, Rank: 20, Reasoning: CDON matches feeding and lethargy but is not metabolic. Gene: PIGQ, Rank: 21, Reasoning: PIGQ is associated with feeding and lethargy, but not with findings consistent with MSUD or abnormal urine odor. Gene: PIGP, Rank: 22, Reasoning: PIGP is linked to feeding and lethargy, not metabolic disease. Gene: CDKL5, Rank: 23, Reasoning: CDKL5 is associated with feeding and lethargy, but not with branched-chain amino acid abnormalities or specific urine odor. Gene: MAGEL2, Rank: 24, Reasoning: MAGEL2 is linked to feeding and lethargy, not characteristic of metabolic disorders causing elevated branched-chain amino acids. Gene: TG, Rank: 25, Reasoning: TG is tied to feeding difficulties and lethargy, no link with metabolic features. Gene: TGIF1, Rank: 26, Reasoning: TGIF1 matches feeding and lethargy, no metabolic link. Gene: TIMMDC1, Rank: 27, Reasoning: TIMMDC1 is linked to feeding and lethargy, lacks specificity for metabolic involvement as in this scenario. Gene: CASK, Rank: 28, Reasoning: CASK matches feeding and lethargy, not known for metabolic disease. Gene: MCCC1, Rank: 29, Reasoning: MCCC1 is linked to feeding and lethargy. While MCC deficiency can have odor and metabolic findings, it is much less associated with branched chain aminoacidemia compared to MSUD. Gene: BTD, Rank: 30, Reasoning: BTD is tied to feeding and lethargy, associated with biotinidase deficiency, not primary branched-chain amino acid metabolism. Starting variant search... Querying variants with filters: Gene: BCKDHA Consequence: missense_variant, frameshift_variant, stop_gained, splice_donor_variant, splice_acceptor_variant Max gnomAD frequency: 0.005 Limit: 20, Offset: 0 Total variants matching filters: 1 Fetched 1 variants starting at offset 0 Variant search completed. Results: We identified a single, rare, biallelic-inactivating variant in BCKDHA that is diagnostic for autosomal recessive Maple Syrup Urine Disease Type 1A. 1) BCKDHA NM_000709.3:c.5del - Consequence: frameshift_variant (p.(Val2Trpfs*?) ) - gnomAD v4.0 allele frequency: 0.0 - ClinVar: not previously reported - Patient genotype: 1/1 (homozygous alternate; total depth 19×, allele depths 0/19) - Maternal genotype: 0/1 (heterozygous carrier) - Paternal genotype: 0/1 (heterozygous carrier) Interpretation - The patient is homozygous for a novel frameshift deletion near the N-terminus of BCKDHA, predicted to abolish normal protein function. - Both parents are heterozygous carriers, consistent with autosomal recessive inheritance. - Loss-of-function variants in BCKDHA are a well-established cause of Maple Syrup Urine Disease, matching the patient's elevated branched-chain amino acids, feeding difficulties, lethargy and "sweet, burnt-sugar" odor. Conclusion This homozygous BCKDHA frameshift variant provides a molecular diagnosis of Maple Syrup Urine Disease (MSUD) Type 1A. Given the low genotype quality (GQ 4) for the proband, we recommend confirmation by orthogonal testing (e.g., Sanger sequencing) and prompt initiation or continuation of appropriate metabolic management.