Diamond Blackfan anemia (DBA), a syndrome primarily characterized by anemia and physical abnormalities, is one among a group of related inherited bone marrow failure syndromes (IBMFS) which share overlapping clinical features. Heterozygous mutations or single-copy deletions have been identified in 12 ribosomal protein genes in approximately 60% of DBA cases, with the genetic etiology unexplained in most remaining patients. Unlike many IBMFS, for which functional screening assays complement clinical and genetic findings, suspected DBA in the absence of typical alterations of the known genes must frequently be diagnosed after exclusion of other IBMFS. We report here a novel deletion in a child that presented such a diagnostic challenge and prompted development of a novel functional assay that can assist in the diagnosis of a significant fraction of patients with DBA. The ribosomal proteins affected in DBA are required for pre-rRNA processing, a process which can be interrogated to monitor steps in the maturation of 40S and 60S ribosomal subunits. In contrast to prior methods used to assess pre-rRNA processing, the assay reported here, based on capillary electrophoresis measurement of the maturation of rRNA in pre-60S ribosomal subunits, would be readily amenable to use in diagnostic laboratories. In addition to utility as a diagnostic tool, we applied this technique to gene discovery in DBA, resulting in the identification of RPL31 as a novel DBA gene.

Pompe disease (PD) is a type of lysosomal storage disorder, in which the glycogen stored in lysosomes begins to accumulate due to deficiency of the enzyme acid alpha-glucosidase (GAA) (Barba-Romero et al., 2012). Deficiency of GAA causes accumulation of glycogen in skeletal, cardiac and smooth muscles leading to a clinical spectrum of PD. There is a high degree of variability among individuals affected with PD seen in age of onset, rate of disease progression and clinical phenotype (Chan et al., 2017). This condition is inherited in an autosomal recessive manner with incidences ranging from 1:14,000 in African Americans to 1:100,000 in individuals of European descent (Kishnani et al., 2012).Two broad subtypes have been classified clinically, depending on age of onset (before or after 1 year of age of the patient) and the residual GAA activity (Chan et al., 2017;Dasouki et al., 2014).Classic infantile-onset Pompe disease (IOPD) is a rapidly progressing form that can present shortly after birth with cardiomyopathy, cardiorespiratory failure, and death within the first year of life due to a lower concentration of GAA (Chan et al., 2017). Late-onset Pompe

We present a patient with a complex phenotype including diagnoses of Ebstein's anomaly and Prader–Willi syndrome (PWS) as well as additional congenital anomalies and genetic variants with potential clinical effects. This is the first reported case of both diagnoses present in the same patient. The diagnosis of Ebstein's anomaly was made on prenatal ultrasound. She presented with neonatal hypotonia, feeding problems, and dysmorphic features, followed by later onset weight gain, leading to a diagnosis of PWS. Further evaluations revealed Blaschkoid hyperpigmentation, laryngeal cleft, and pigmentary retinopathy. Whole exome sequencing determined a likely pathogenic variant in alkaline phosphatase gene and several mitochondrial DNA variants. We discuss the known genetic mechanisms of PWS and compare them to the heterogenous genetic associations of Ebstein's anomaly. The standard of care treatment for PWS is growth hormone therapy, which is associated with right-sided heart failure risks. This case illustrates the need to complete the diagnostic work up in all patients, as well as the necessity of a multidisciplinary approach for optimal outcomes.

No abstract