To present our experience using a multiomic approach, which integrates genetic and biochemical testing as a first-line diagnostic tool for patients with inherited metabolic disorders (IMDs). A cohort of 3720 patients from 62 countries was tested using a panel including 206 genes with single nucleotide and copy number variant (SNV/CNV) detection, followed by semi-automatic variant filtering and reflex biochemical testing (25 assays). In 1389 patients (37%), a genetic diagnosis was achieved. Within this cohort, the highest diagnostic yield was obtained for patients from Asia (57.5%, mainly from Pakistan). Overall, 701 pathogenic/likely pathogenic unique SNVs and 40 CNVs were identified. In 620 patients, the result of the biochemical tests guided variant classification and reporting. Top five diagnosed diseases were: Gaucher disease, Niemann-Pick disease type A/B, phenylketonuria, mucopolysaccharidosis type I, and Wilson disease. We show that integrated genetic and biochemical testing facilitated the decision on clinical relevance of the variants and led to a high diagnostic yield (37%), which is comparable to exome/genome sequencing. More importantly, up to 43% of these patients (n = 610) could benefit from medical treatments (e.g., enzyme replacement therapy). This multiomic approach constitutes a unique and highly effective tool for the genetic diagnosis of IMDs.

KBG syndrome is characterised by distinctive facial gestalt, short stature and variable clinical findings. With ageing, some features become more recognizable, allowing a differential diagnosis. We aimed to better characterise natural history of KBG syndrome. In the context of a European collaborative study, we collected the largest cohort of KBGS patients (49). A combined array-CGH and NGS approach investigated both genomic CNVs/SNVs. Intellectual disability (ID) (82%) ranged from mild to moderate with severe ID identified in two patients. Epilepsy was present in 26.5%. Short stature was consistent over time, while OFC (median value: −0.88 SD at birth) normalised over years. Cerebral anomalies, were identified in 56% of patients and thus represented the second most relevant clinical feature reinforcing clinical suspicion in the paediatric age when short stature and vertebral/dental anomalies are vague. Macrodontia, oligodontia, and dental agenesis (53%) were almost as frequent as skeletal anomalies, such as brachydactyly, short fifth finger, fifth finger clinodactyly, pectus excavatum/carinatum, delayed bone age. In 28.5% of individuals, prenatal ultrasound anomalies were reported. Except for three splicing variants, leading to a premature termination, variants were almost all frameshift. Our results, broadening the spectrum of KBGS phenotype progression, provide useful tools to facilitate differential diagnosis and improve clinical management. We suggest to consider a wider range of dental anomalies before excluding diagnosis and to perform a careful odontoiatric/ENT evaluation in order to look for even submucosal palate cleft given the high percentage of palate abnormalities. NGS approaches, following evidence of antenatal ultrasound anomalies, should include ANKRD11.

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Tuberous Sclerosis is a complex genetic disease that has well-defined clinical criteria. These criteria don't include pancreatic neuroendocrine tumors. We represent a rare case of a patient, with a non–functioning pancreatic neuroendocrine tumor and concomitant diagnosis of tuberous sclerosis complex, and basement membrane disease. The patient was diagnosed based on typical radiologic findings. We have suggested close monitoring and during follow-up studies, the disease was stable. Interestingly the patient tested negative for Tuberous Sclerosis Complex (TSC), which suggests that she might be a somatic mosaic and the mutation level in blood lymphocytes was below the detection level. Moreover, a heterozygous pathogenic variant p.(Gly774Arg) and a heterozygous likely pathogenic variant p.(Gly1465Asp) were identified in the COL4A4 gene. COL4A4 gene is responsible for causing autosomal dominant basement membrane disease. In this case report, we discuss clinical, radiologic, and genetic aspects of these diseases, as well as optimal treatment and follow-up strategies. Thus, by presenting this case we would like to increase awareness of pancreatic neuroendocrine tumors in TSC and emphasize the need for follow-up monitoring.

Chromosome 9p duplication, also known as a partial trisomy 9p, is a rare chromosome abnormality due to a duplication of the partial short arm of chromosome 9. More than 200 cases are reported in the literature. Major clinical findings include short stature, developmental delay, intellectual disability, and characteristic facial dysmorphic features. The most common origin of this syndrome is malsegregation of a parental reciprocal translocation. Only about 25 cases are reported as de novo in the literature, the rest being inherited from asymptomatic balanced carrier parents. We report an additional new case of de novo partial trisomy 9p in an 8-year-old girl, and describe her clinical manifestations and diagnostic testing results.