Mendelian Genetics

Research Overview

The identification and functional evaluation of hearing loss genes in diverse populations: Approximately 1-2 in every 1,000 newborns in developed countries suffers from hearing impairment (HI), which is often attributable to genetic factors. Via a family-based study design that implements exome/genome sequencing, our research team has a long-standing history of studying the genetic etiology of HI in various populations, including Pakistani, Hungarian, Romani, and diverse sub-Saharan African populations. Little is known about the allelic architecture and frequency of HI-causal variants in sub-Saharan Africans and African-Americans. Identification of genes and variants involved in HI in diverse populations is important to improve and tailor genetic testing in each population. Improved and early diagnosis can maximize a child’s cognitive, social emotional, speech and language development.

Unraveling the genetic basis of congenital malformations of the hearing system: Hearing impairment is a common and disabling sensory defect which in a subset of individuals can be due to an abnormal cochleovestibular anatomy. Cochleovestibular (CV) and cochleovestibular nerve (CVN) anomalies can significantly impact a child’s development and currently pose challenges in treatment and management. Unfortunately, the molecular basis of non-syndromic severe CV malformations and/or abnormal CVNs has scarcely been studied. Our research leverages genomics data and temporal bone imaging data to unravel the molecular basis of non-syndromic CV/CVN malformations. Preliminary data has suggested that the etiology of these malformations is greatly driven by de novo variants; as such, our research focuses on a trio-based (parent-affected child) study design.

The genetic etiology of neurodevelopmental disorders with intellectual disability: Neurodevelopmental disorders (NDDs) comprise of a group of disorders associated with abnormal brain development. NDDs with intellectual disability (ID), characterized by significant limitations in intellectual functioning and adaptive behavior, affect 1% of the population globally and pose a significant public health burden on society. The underlying neuronal mechanisms of dysregulation that trigger NDD onset and progression are not fully understood. Rare genetic variants have been shown to play a key role in their development, especially in those NDDs which are severe in nature. Our research is focused on using exome and genome sequencing to study the genetic etiology of severe NDDs in diverse populations, including founder populations (Finnish, Romani) and understudied populations (sub-Saharan African), in parent-affected child trios and larger families.

Epilepsy genetics: Epilepsy is one of the most common neurological disorders. Although also often present in severe NDDs studied above, our team also focuses on investigating large families with non-syndromic epilepsy/seizures in understudied populations via exome and genome sequencing.

The genetic etiology of limb anomalies: Limb development consists of a complex and precise interaction of various genes. There is a large phenotypic variety of congenital limb malformations, which may be isolated or syndromic, including chondrodysplasia punctata, brachydactyly, syndactyly and polydactyly. The wealth of knowledge obtained from genetic causes of congenital limb anomalies have substantially improved classification of disorders and understanding of limb development and evolution. Our team uses next-generation sequencing approaches to study limb anomalies in families affected with these disorders.

Improving genetic diagnosis in genomic cold cases: Etiological diagnosis in pediatric disease is imperative for disease management, counseling, prognosis, treatment, prevention, and quality of life. Due to the lack of powerful diagnostic tools, several parents of children with severe disorders often endure years-long diagnostic odysseys of trial-and-error testing with inconclusive results and misdirected treatments. Unfortunately, current genetic testing leaves many cases undiagnosed. Our team is exploring various methods to improve genetic diagnosis for various Mendelian disorders:

1. Via integrating various “-omics” technologies, including genomics, transcriptomics and epigenomics.
2. By exploring “genomic dark matter” via novel genomic techniques. Similar to the “dark matter” of the universe, this part of the genome is currently difficult to detect and understand with current standard sequencing techniques (due to repeats and high/low GC content). However, “dark matter” covers a significant part (>50%) of the human genome and many regions are likely clinically relevant. We are using novel methods, including optical genome mapping, artificial long-read sequencing and long-read sequencing to study these difficult to assess regions in the human genome, and understand their role in disease.

Other Mendelian diseases of interest: We also study the genetic etiology of a variety of other Mendelian disorders, including infertility, ectodermal disorders, cardiac diseases, vision disorders and familial neurodegenerative disorders.

If you are interested in joining our team related to any of these projects, please contact us at: is2632@cumc.columbia.edu; sml3@cumc.columbia.edu.