Biology subjects

Michael J Bamshad

Publications and source records attributed to Michael J Bamshad.

4 recordsLinked to original sources

bioRxiv2016

Recessive inactivating mutations in TBCK, encoding a Rab GTPase-activating protein that modulates mTOR signaling, cause severe infantile syndromic encephalopathy

Infantile encephalopathies are a group of clinically and biologically heterogeneous disorders for which the genetic basis remains largely unknown. Here, we report a previously unrecognized syndromic neonatal encephalopathy characterized by profound developmental disability, severe hypotonia, seizures, diminished respiratory drive requiring mechanical ventilation, brain atrophy, corpus callosum dysgenesis, cerebellar vermis hypoplasia, and facial dysmorphism. Biallelic inactivating mutations in TBCK (TBC1 domain-containing kinase) were independently identified by Whole-Exome Sequencing (WES) as the cause of this condition in four unrelated families. Matching these families was facilitated by sharing phenotypic profiles and WES data in a recently released web-based tool (Geno2MP) that links phenotypic information to rare variants in families with Mendelian traits. TBCK is a putative GTPase-activating protein (GAP) for small GTPases of the Rab family and has been shown to control cell growth and proliferation, actin cytoskeleton dynamics, and mTOR signaling. Two of the three mutations are predicted to truncate the protein (c.376C>T [p.Arg126*] and c.1363A>T [p.Lys455*]), and loss of the major TBCK isoform was confirmed in primary fibroblasts from one affected individual. The third mutation, c.1532G>A [p.Arg511His], alters a conserved residue within the TBC1 domain. Structural analysis implicates Arg511 as a required residue for Rab-GAP function, and in silico homology modeling predicts impaired GAP function in the corresponding mutant. These results suggest loss of Rab-GAP activity is the underlying mechanism of disease. In contrast to other disorders caused by dysregulated mTOR signaling associated with focal or global brain overgrowth, impaired TBCK function results in progressive loss of brain volume.

Genetics↗

bioRxiv2015

Gene discovery for Mendelian conditions via social networking: de novo variants in KDM1A cause developmental delay and distinctive facial features

Purpose:The pace of Mendelian gene discovery is slowed by the \"n-of-1 problem\" - the difficulty of establishing causality of a putatively pathogenic variant in a single person or family. Identification of an unrelated person with an overlapping phenotype and suspected pathogenic variant in the same gene can overcome this barrier but is often impeded by lack of a convenient or widely-available way to share data on candidate variants / genes among families, clinicians and researchers.\n\nMethods:Social networking among families, clinicians and researchers was used to identify three children with variants of unknown significance in KDM1A and similar phenotypes.\n\nResults:De novo variants in KDM1A underlie a new syndrome characterized by developmental delay and distinctive facial features.\n\nConclusion:Social networking is a potentially powerful strategy to discover genes for rare Mendelian conditions, particularly those with non-specific phenotypic features. To facilitate the efforts of families to share phenotypic and genomic information with each other, clinicians, and researchers, we developed the Repository for Mendelian Genomics Family Portal (RMD-FP). Design and development of a web-based tool, MyGene2, that enables families, clinicians and researchers to search for gene matches based on analysis of phenotype and exome data deposited into the RMD-FP is underway.

Genetics↗

bioRxiv2015

Autosomal dominant multiple pterygium syndrome is caused by mutations in MYH3

Multiple pterygium syndromes (MPS) are a phenotypically and genetically heterogeneous group of rare Mendelian conditions characterized by multiple pterygia, scoliosis and congenital contractures of the limbs. MPS typically segregates as an autosomal recessive disorder but rare instances of autosomal dominant transmission have been reported. While several mutations causing recessive MPS have been identified, the genetic basis of dominant MPS remains unknown. We identified four families with dominantly transmitted MPS characterized by pterygia, camptodactyly of the hands, vertebral fusions, and scoliosis. Exome sequencing identified predicted protein-altering mutations in embryonic myosin heavy chain (MYH3) in three families. MYH3 mutations underlie distal arthrogryposis types 1, 2A and 2B, but all mutations reported to date occur in the head and neck domains. In contrast, two of the mutations found to cause MPS occurred in the tail domain. The phenotypic overlap among persons with MPS coupled with physical findings distinct from other conditions caused by mutations in MYH3, suggests that the developmental mechanism underlying MPS differs from other conditions and / or that certain functions of embryonic myosin may be perturbed by disruption of specific residues / domains. Moreover, the vertebral fusions in persons with MPS coupled with evidence of MYH3 expression in bone suggests that embryonic myosin plays a previously unknown role in skeletal development.

Genetics↗

bioRxiv2015

De novo Mutations in NALCN Cause a Syndrome of Congenital Contractures of the Limbs and Face with Hypotonia, and Developmental Delay

Freeman-Sheldon syndrome, or distal arthrogryposis type 2A (DA2A), is an autosomal dominant condition caused by mutations in MYH3 and characterized by multiple congenital contractures of the face and limbs and normal cognitive development. We identified a subset of five simplex cases putatively diagnosed with \"DA2A with severe neurological abnormalities\" in which the proband had Congenital Contractures of the LImbs and FAce, Hypotonia, and global Developmental Delay often resulting in early death, a unique condition that we now refer to as CLIFAHDD syndrome. Exome sequencing identified missense mutations in sodium leak channel, nonselective (NALCN) in four families with CLIFAHDD syndrome. Using molecular inversion probes to screen NALCN in a cohort of 202 DA cases as well as concurrent exome sequencing of six other DA cases revealed NALCN mutations in ten additional families with \"atypical\" forms of DA. All fourteen mutations were missense variants predicted to alter amino acid residues in or near the S5 and S6 pore-forming segments of NALCN, highlighting the functional importance of these segments. In vitro functional studies demonstrated that mutant NALCN nearly abolished the expression of wildtype NALCN, suggesting that mutations that cause CLIFAHDD syndrome have a dominant negative effect. In contrast, homozygosity for mutations in other regions of NALCN has been reported in three families with an autosomal recessive condition characterized mainly by hypotonia and severe intellectual disability. Accordingly, mutations in NALCN can cause either a recessive or dominant condition with varied though overlapping phenotypic features perhaps depending on the type of mutation and affected protein domain(s).

Genetics↗