Unraveling mucolipidosis type III gamma through whole genome sequencing in late-onset retinitis pigmentosa: a case report.

BACKGROUND: We describe the case of a 47-year-old man referred to a retinal clinic and diagnosed with late-onset retinitis pigmentosa. Surprisingly, genetic testing revealed compound heterozygous pathogenic variants in GNPTG, leading to the diagnosis of the autosomal recessive lysosomal storage disorder mucolipidosis type III gamma. Mucolipidosis type III gamma is typically diagnosed during childhood due to symptoms relating to skeletal dysplasia. Retinal dystrophy is not a common phenotypic feature. CASE PRESENTATION: Ophthalmologic examination was consistent with a mild form of retinitis pigmentosa and included fundus photography, measurement of best-corrected visual acuity, optical coherence tomography, electroretinogram and visual field testing. Extraocular findings included joint restriction and pains from an early age leading to bilateral hip replacement by age 30, aortic insufficiency, and hypertension. Genetic analysis was performed by whole genome sequencing filtered for a gene panel of 325 genes associated with retinal disease. Two compound heterozygous pathogenic variants were identified in GNPTG, c.347_349del and c.607dup. The diagnosis of mucolipidosis type III gamma was confirmed biochemically by measurement of increased activities of specific lysosomal enzymes in plasma. CONCLUSION: To our knowledge this is the first description of retinitis pigmentosa caused by compound heterozygous variants in GNPTG, providing further indications that late-onset retinal dystrophy is part of the phenotypic spectrum of mucolipidosis type III gamma.

Oesophageal atresia with tracheoesophageal fistula and anal atresia in a patient with a de novo microduplication in 17q12.

Oesophageal atresia (OA) and tracheoesophageal fistula (TOF) are foregut malformations with a heterogeneous etiology. OA/TOF may occur as an isolated anomaly or as part of a syndrome. Chromosomal anomalies have been reported in 6-10% of OA/TOF. Several genes have been implicated in cases of syndromic OA/TOF, but no single specific chromosomal and monogenic defect has been confirmed as a main etiological factor. We described a patient with a 1.4 Mb duplication at 17q12 detected by SNP-array study and validated using qRT-PCR, who presented with an oesophageal atresia accompanied with tracheoesophageal fistula and anal atresia as well as other symptoms resembling VATER association (thumb hypoplasia, sacral bone defect, cryptorchidism). Genomic rearrangements of chromosome 17q12 are associated with a variety of clinical phenotypes. Only few cases with OA patients with the duplication in 17q12 have been reported. The 17q12 region comprised 15 genes. We propose to consider a role for selected genes such as AATF (cell proliferation and apoptosis) and TADA2L (Wnt pathway) at the 17q12 region as well as developmental and transcriptional pathways represented by these genes, in the development of OA/TOF and VATER association.