Anna Newlin

Human TUBB3 Mutations Perturb Microtubule Dynamics, Kinesin Interactions, and Axon Guidance

We report that eight heterozygous missense mutations in TUBB3, encoding the neuron-specific beta-tubulin isotype III, result in a spectrum of human nervous system disorders that we now call the TUBB3 syndromes. Each mutation causes the ocular motility disorder CFEOM3, whereas some also result in intellectual and behavioral impairments, facial paralysis, and/or later-onset axonal sensorimotor polyneuropathy. Neuroimaging reveals a spectrum of abnormalities including hypoplasia of oculomotor nerves and dysgenesis of the corpus callosum, anterior commissure, and corticospinal tracts. A knock-in disease mouse model reveals axon guidance defects without evidence of cortical cell migration abnormalities. We show that the disease-associated mutations can impair tubulin heterodimer formation in vitro, although folded mutant heterodimers can still polymerize into microtubules. Modeling each mutation in yeast tubulin demonstrates that all alter dynamic instability whereas a subset disrupts the interaction of microtubules with kinesin motors. These findings demonstrate that normal TUBB3 is required for axon guidance and maintenance in mammals.

Heterozygous mutations of the kinesin KIF21A in congenital fibrosis of the extraocular muscles type 1 (CFEOM1).

Congenital fibrosis of the extraocular muscles type 1 (CFEOM1; OMIM #135700) is an autosomal dominant strabismus disorder associated with defects of the oculomotor nerve. We show that individuals with CFEOM1 harbor heterozygous missense mutations in a kinesin motor protein encoded by KIF21A. We identified six different mutations in 44 of 45 probands. The primary mutational hotspots are in the stalk domain, highlighting an important new role for KIF21A and its stalk in the formation of the oculomotor axis.

Mosaic trisomy 7 in a patient with pigmentary abnormalities.

Somatic chromosomal mosaicism may present as isolated pigmentary abnormalities or multiple congenital anomalies with mental retardation. Pigmentary lesions are visually dramatic and are differentiated based on appearance when the underlying pathogenesis is not known. It is now clear that mosaicism is responsible for the pigmentary findings in hypomelanosis of Ito (HI) and linear and whorled nevoid hypermelanosis (LWH). Both hypopigmentation and hyperpigmentation have been noted in the same individual, and both LWH and HI can be caused by similar chromosomal abnormalities. Both of these conditions exhibit similar systemic involvement. We present a case of LWH associated with mosaic trisomy 7 and review the relevant literature.

10 rare tumors that warrant a genetics referral.

The number of described cancer susceptibility syndromes continues to grow, as does our knowledge on how to manage these syndromes with the aim of early detection and cancer prevention. Oncologists now have greater responsibility to recognize patterns of cancer that warrant referral for a genetics consultation. While some patterns of common cancers are easy to recognize as related to hereditary cancer syndromes, there are a number of rare tumors that are highly associated with cancer syndromes yet are often overlooked given their infrequency. We present a review of ten rare tumors that are strongly associated with hereditary cancer predisposition syndromes: adrenocortical carcinoma, carcinoid tumors, diffuse gastric cancer, fallopian tube/primary peritoneal cancer, leiomyosarcoma, medullary thyroid cancer, paraganglioma/pheochromocytoma, renal cell carcinoma of chromophobe, hybrid oncocytoic, or oncocytoma histology, sebaceous carcinoma, and sex cord tumors with annular tubules. This review will serve as a guide for oncologists to assist in the recognition of rare tumors that warrant referral for a genetic consultation.

Non-mosaic tetrasomy 9p in a liveborn infant with multiple congenital anomalies : Case report and comparison with trisomy 9p

Tetrasomy of the short(p) arm of chromosome 9 has been reported in few cases. Most of these children present with microbrachycephaly, wide forehead, hypertelorism, lowset, malformed ears, beaked noses, and micrognathia. Additional anomalies include short neck, congenital heart disease, genital abnormalities, multiple limb defects, hypotonia, and early death.

Evaluation of laboratory perspectives on hereditary cancer panels

Genetic counseling and testing for hereditary cancer susceptibility is a rapidly evolving field and partly a result of next-generation sequencing (NGS) allowing analysis of multiple cancer susceptibility genes simultaneously. This qualitative study explored laboratory perspectives on hereditary cancer panels. Semi-structured interviews were conducted with representatives of clinical laboratories offering hereditary cancer panels via NGS. Several themes emerged from the responses pertaining to hereditary cancer panel development, the importance of communication of panel properties with patients, variant reporting policies, and the future of hereditary cancer gene testing. Clinical utility was discussed as primary consideration during panel development. In addition, while participants indicated gene and syndrome overlap prompted panel development in general, laboratories differed in their opinions of whether phenotypic overlap warrants offering pan-cancer panels only versus cancer specific panels. Participants stressed the importance of patients understanding implications of panel testing, including what is tested for and limitations of testing. While all laboratories discussed the limitations of a variant of uncertain significance result, they differed significantly in their reporting methods. This study provides healthcare providers information on the laboratory approach to panel testing, highlighting both commonalities and differences in laboratory approaches, and may allow providers to make more informed decisions when ordering hereditary cancer panels.