Genomic screening in rare disorders: New mutations and phenotypes, highlighting ALG14 as a novel cause of severe intellectual disability

Clinical Genetics
Malin KvarnungElisabeth S Lundberg

Abstract

We have investigated 20 consanguineous families with multiple children affected by rare disorders. Detailed clinical examinations, exome sequencing of affected as well as unaffected family members and further validation of likely pathogenic variants were performed. In 16/20 families, we identified pathogenic variants in autosomal recessive disease genes (ALMS1, PIGT, FLVCR2, TFG, CYP7B1, ALG14, EXOSC3, MEGF10, ASAH1, WDR62, ASPM, PNPO, ERCC5, KIAA1109, RIPK4, MAN1B1). A number of these genes have only rarely been reported previously and our findings thus confirm them as disease genes, further delineate the associated phenotypes and expand the mutation spectrum with reports of novel variants. We highlight the findings in two affected siblings with splice altering variants in ALG14 and propose a new clinical entity, which includes severe intellectual disability, epilepsy, behavioral problems and mild dysmorphic features, caused by biallelic variants in ALG14.

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Citations

Apr 24, 2020·Clinical Endocrinology·Jakob DalJens Otto L Jørgensen
Jul 14, 2020·Clinical Dysmorphology·Anna Uhrova MeszarosovaDana Safka Brozkova
Feb 26, 2019·Nature Medicine·Giedre GrigelionieneTatsuya Kobayashi
Oct 15, 2019·Frontiers in Genetics·Malin KvarnungAnna Falk
Jun 28, 2020·BMC Medical Genetics·Kishore KumarBabylakshmi Muthusamy
Oct 30, 2020·Nucleic Acids Research·Isabela Fraga de AndradeEmery H Bresnick
Mar 23, 2021·American Journal of Medical Genetics. Part a·Flavia PalomboValerio Carelli

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