Genomic analysis of primordial dwarfism reveals novel disease genes

Abstract

Primordial dwarfism (PD) is a disease in which severely impaired fetal growth persists throughout postnatal development and results in stunted adult size. The condition is highly heterogeneous clinically, but the use of certain phenotypic aspects such as head circumference and facial appearance has proven helpful in defining clinical subgroups. In this study, we present the results of clinical and genomic characterization of 16 new patients in whom a broad definition of PD was used (e.g., 3M syndrome was included). We report a novel PD syndrome with distinct facies in two unrelated patients, each with a different homozygous truncating mutation in CRIPT. Our analysis also reveals, in addition to mutations in known PD disease genes, the first instance of biallelic truncating BRCA2 mutation causing PD with normal bone marrow analysis. In addition, we have identified a novel locus for Seckel syndrome based on a consanguineous multiplex family and identified a homozygous truncating mutation in DNA2 as the likely cause. An additional novel PD disease candidate gene XRCC4 was identified by autozygome/exome analysis, and the knockout mouse phenotype is highly compatible with PD. Thus, we add a number of novel genes to the growing list of PD-linked genes, including one which we show to be linked to a novel PD syndrome with a distinct facial appearance. PD is extremely heterogeneous genetically and clinically, and genomic tools are often required to reach a molecular diagnosis.

Accelerating matchmaking of novel dysmorphology syndromes through clinical and genomic characterization of a large cohort

“…30 This may suggest a different disease mechanism than we have previously shown for other genes in which biallelic loss of function results in distinct clinical phenotypes as compared with heterozygous mutations. 9,31,32 Alternatively, the susceptibility to absence seizures may have been erroneous.…”

“…For example, we have published the identification of several novel candidate genes in the setting of retinal dystrophy and primordial dwarfism, and some of these genes have since been independently verified by others. [7][8][9] Recently, we published the identification of 33 novel candidate genes for various neurocognitive phenotypes, and at least 6 of these were independently found to be mutated by other investigators in the few months since the article appeared online (unpublished data). 10 However, we are not aware of any similar effort to accelerate the discovery of novel candidate genes specifically in the setting of dysmorphology syndromes.…”

Programmed DNA breaks in lymphoid cells: repair mechanisms and consequences in human disease

“…A mutation in XRCC4 identified by exome sequencing suggested this gene as a candidate disease‐causing mutation in a patient with primordial dwarfism 68. Most recently, XRCC4 mutations were identified within five families in patients with microcephalic primordial dwarfism 69.…”

New Genetic Diagnoses of Short Stature Provide Insights into Local Regulation of Childhood Growth

“…Mutations in XRCC4 cause a new syndrome named SSMED, which stands for short stature, microcephaly, and endocrine dysfunction [138, 153, 154]. The XRCC4 gene encodes a protein that functions together with DNA ligase IV and the DNA-dependent protein kinase in the repair of DSB.…”

“…SCKL2 is caused by mutations in RBBP8 ( CTIP ), which encodes a nuclear protein that regulates cell proliferation and may itself be a tumor suppressor acting in the same pathway as BRCA1 in transcriptional regulation, DNA repair, and/or cell cycle checkpoint control [137]. Mutations in DNA2 , a member of the DNA2/NAM7 helicase family, are involved in the maintenance of mitochondrial and nuclear DNA stability and have been found as the cause of SCKL8 [138]. Recently, identification of mutations in the TRAIP gene, encoding an E3 RING ubiquitin ligase, cause SCKL9 .…”