Rare, atypical, and undiagnosed autosomal-recessive disorders frequently occur in the offspring of consanguineous couples. Current routine diagnostic genetic tests fail to establish a diagnosis in many cases. We employed exome sequencing to identify the underlying molecular defects in patients with unresolved but putatively autosomal-recessive disorders in consanguineous families and postulated that the pathogenic variants would reside within homozygous regions. Fifty consanguineous families participated in the study, with a wide spectrum of clinical phenotypes suggestive of autosomal-recessive inheritance, but with no definitive molecular diagnosis. DNA samples from the patient(s), unaffected sibling(s), and the parents were genotyped with a 720K SNP array. Exome sequencing and array CGH (comparative genomic hybridization) were then performed on one affected individual per family. High-confidence pathogenic variants were found in homozygosity in known disease-causing genes in 18 families (36%) (one by array CGH and 17 by exome sequencing), accounting for the clinical phenotype in whole or in part. In the remainder of the families, no causative variant in a known pathogenic gene was identified. Our study shows that exome sequencing, in addition to being a powerful diagnostic tool, promises to rapidly expand our knowledge of rare genetic Mendelian disorders and can be used to establish more detailed causative links between mutant genotypes and clinical phenotypes.

Next‐generation sequencing (NGS) has been instrumental in solving the genetic basis of rare inherited diseases, especially neurodevelopmental syndromes. However, functional workup is essential for precise phenotype definition and to understand the underlying disease mechanisms. Using whole exome (WES) and whole genome sequencing (WGS) in four independent families with hypotonia, neurodevelopmental delay, facial dysmorphism, loss of white matter, and thinning of the corpus callosum, we identified four previously unreported homozygous truncating PPP1R21 alleles: c.347delT p.(Ile116Lysfs*25), c.2170_2171insGGTA p.(Ile724Argfs*8), c.1607dupT p.(Leu536Phefs*7), c.2063delA p.(Lys688Serfs*26) and found that PPP1R21 was absent in fibroblasts of an affected individual, supporting the allele's loss of function effect. PPP1R21 function had not been studied except that a large scale affinity proteomics approach suggested an interaction with PIBF1 defective in Joubert syndrome. Our co‐immunoprecipitation studies did not confirm this but in contrast defined the localization of PPP1R21 to the early endosome. Consistent with the subcellular expression pattern and the clinical phenotype exhibiting features of storage diseases, we found patient fibroblasts exhibited a delay in clearance of transferrin‐488 while uptake was normal. In summary, we delineate a novel neurodevelopmental syndrome caused by biallelic PPP1R21 loss of function variants, and suggest a role of PPP1R21 within the endosomal sorting process or endosome maturation pathway.

Lysosomal storage disorders (LSD) are rare entities of recessive inheritance.

Congenital disorders of manganese metabolism are rare occurrences in children, and medical management of these disorders is complex and challenging. Homozygous exonic mutations in the manganese transporter SLC39A14 have recently been associated with a pediatric-onset neurodegenerative disorder characterized by brain manganese accumulation and clinical signs of manganese neurotoxicity, including parkinsonism-dystonia. We performed whole exome sequencing on DNA samples from two unrelated female children from the United Arab Emirates with progressive movement disorder and brain mineralization, identified a novel homozygous intronic mutation in SLC39A14 in both children, and demonstrated that the mutation leads to aberrant splicing. Both children had consistently elevated serum manganese levels and were diagnosed with SLC39A14-associated manganism. Over a four-year period, we utilized a multidisciplinary management approach for Patient 1 combining decreased manganese dietary intake and chelation with symptomatic management of dystonia. Our treatment strategy appeared to slow disease progression, but did not lead to a cure or reversal of already established deficits. Clinicians should consider testing for noncoding mutations in the diagnosis of congenital disorders of manganese metabolism and utilizing multidisciplinary approaches in the management of these disorders.

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BackgroundThis study reports on the use of whole exome sequencing (WES) to diagnose children with inborn errors of metabolism and other disorders in United Arab Emirates.MethodsFrom January 2012 to December 2014, 85 patients (46 % females) were seen in the metabolic center at Tawam Hospital (Abu Dhabi) and WES testing was requested because definitive diagnoses were not reached by conventional methods.ResultsEighty (93 %) patients were <18 years old and 44 (52 %) were <5 years. Sixty-eight (80 %) patients had neurologic abnormalities. WES facilitated rapid diagnosis in 50 % of the patients, especially those with mitochondrial disorders. Yet, in most cases extensive investigation was required after the results were available. Most patients with confirmed molecular diagnoses had autosomal recessive disorders and were homozygous for the rare alleles. Most patients with autosomal dominant disorders and all patients with X-linked disorders had de novo mutations. WES results were negative (no pathogenic variants related to patient phenotype were identified) in six patients and incorrect in two patients. One patient had a reported “deleterious” hemizygous mutation in SLC35A2, c.617_620del (p.Q206fs), suggesting ‘congenital disorder of glycosylation, TYPE IIm’, but glycosylation studies were normal and healthy brothers had the same mutation. Another patient had “pathogenic” mutation in MCCC2, c.1015G > A (p.V339M), but urine organic acids was normal. WES confirmed inborn errors of metabolism (five mitochondrial diseases, three lysosomal storage diseases, and six other disorders) in 14 patients and genetic disorders (14 neurological diseases and three non-neurological diseases) in 17 patients. Variants of unknown significance were identified in 48 patients; 12 had “confirmed pathologic variants”and 12 had “likely pathologic variants”, based on consistent phenotypes, biochemical/ segregation studies, or reported pathogenicity. In 24 patients, the variants were inconsistent with phenotypes or biochemical/ familial studies.ConclusionsAlthough WES provided molecular diagnoses, the results required careful interpretations and many patients required additional investigations. This tool is useful when conventional diagnostic methods fail. Staff competence in obtaining consent/ permission, interpreting the findings, and providing the proper counseling are essential before incorporating this technology into routine clinical practices.

BackgroundInherited intellectual disability (ID) conditions are a group of genetically heterogeneous disorders that lead to variable degrees of cognition deficits. It has been shown that inherited ID can be caused by mutations in over 100 different genes and there is evidence for the presence of as yet unidentified genes in a significant proportion of patients. We aimed at identifying the defective gene underlying an autosomal recessive ID in two sibs of an Emirati family.MethodsA combined approach involving homozygosity mapping and whole-exome sequencing was used to identify the causative mutation. RNA analysis was performed to gain further insight into the pathogenic effect of the detected mutation.ResultsWe have identified a homozygous splicing mutation (c.1219_1222+1delAAAGG) in the LINS gene in the affected children. LINS is the human homologue of the Drosophila segment polarity gene lin that encodes an essential regulator of the wingless/Wnt signaling. The identified mutation alters the first consensus nucleotide of the 5' donor splice junction of intron 5 and the 3' end of exon 5. Transcript analysis revealed that this change leads to an exon skipping event resulting in direct splicing of exon 4 to exon 6. Another mutation in LINS has been described very briefly in an Iranian family with autosomal recessive ID and microcephaly.ConclusionOur study confirms that LINS, a modulator of the WNT pathway, is an indispensable gene to human cognition and this finding sheds further light on the importance of WNT signaling in human brain development and/or function.

The above findings support the premise that biallelic mutations in TALDO1 are responsible for transaldolase deficiency and confirm the broad phenotypic variability of this condition, even with the same genotype.