This page is dedicated to the Brain Malformations research study, one of 57 studies supported by the Boston Children’s Rare Disease Collaborative (CRDC). For more information about the CRDC, please visit our home page. Established in 2018, the CRDC supports pediatric rare disease research and provides families with genetic diagnoses that enable personalized treatments, including precision medicine and targeted therapies.

The Brain Malformations research study, established at Boston Children’s in 2022 and led by Drs. Christopher Walsh and Diane Shao, has so far enrolled 20 patients and their families. The study aims to identify genetic causes of brain malformations and provide personalized medicine.

Disease information

Brain malformations are a group of disorders that affect brain development or brain structure and include:

  • Focal Cortical Dysplasia
  • Hemimegalencephaly
  • Heterotopia
  • Interhemispheric Cysts With Agenesis of the Corpus Callosum
  • Joubert Syndrome
  • Lissencephaly
  • Microcephaly
  • Pachygyria
  • Polymicrogyria
  • Schizencephaly
  • Walker-Warburg Syndrome

It is estimated that 30-80% of individuals with brain malformations have an underlying genetic cause for their condition. Learn more about brain malformations seen at Boston Children’s.

Key outcomes

Already, their group has identified diagnostic variants in 18 percent of patients, including one with gray matter heterotopia. 67 percent of patients with diagnostic results have had changes in care delivery and an additional 29 percent have candidate findings that are being further researched.

Genes identified in study patients

ACOX2 ARX ATP2B3 B4GALNT4 CFAP54 CHD3 CUL5 DLL1 DMXL1 DOCK8 EMC2 EPHA3 ES GRAMD1B GRID2 HECW2 KIF20A KRIT1 LIS MTSS1L MTSS2 MYO3B NDUFAF6 NEDD4 NEURL4 NTN PAFAH1B1 POLR2A POMT1 REXO1 RTTN SETD1B SQLE ST13 STMN2 STXBP1 TAGLN TRIO TUBB4B USP19 USP9X VUS WDR37

Participate in research

Physicians may refer their patients with diagnoses of brain malformations to Dr. Walsh and Dr. Shao. Once study eligibility is confirmed, a research coordinator will reach out to the family to consent and enroll them. Read more about Dr. Walsh’s and Dr. Shao’’s studies, including the Brain Malformation study, on the Walsh lab webpage and Dr. Shao's research profile.

Patient care

Patients and their families with brain malformations can be seen by an expert multidisciplinary team in the Brain Development and Genetics Clinic at Boston Children’s. Learn more about brain malformations. 

Investigators

Divisions

Notable publications by investigators

  1. Exome Sequencing and the Identification of New Genes and Shared Mechanisms in Polymicrogyria.
  2. A recurrent de novo variant in NUSAP1 escapes nonsense-mediated decay and leads to microcephaly, epilepsy, and developmental delay.
  3. Loss of non-motor kinesin KIF26A causes congenital brain malformations via dysregulated neuronal migration and axonal growth as well as apoptosis.
  4. Polymicrogyria is Associated With Pathogenic Variants in PTEN.
  5. Perinatal Reduction of Genetically Aberrant Neurons from Human Cerebral Cortex.

Patient stories

In 2023, Dr. Shao evaluated a four-year-old boy presenting with cognitive impairments and lissencephaly, a brain malformation characterized by a smooth back of the brain. Although previous whole exome sequencing did not yield a clear diagnosis, the team recognized a classic pattern for one particular genetic form of lissencephaly caused by the PAFAH1B1 gene (also known as LIS1). Suspecting a mutation in an overlooked region of the gene, the team made a groundbreaking discovery: the patient had a mutation affecting the part of the gene before protein creation started. This finding not only provided the family with a long-awaited definitive diagnosis but also introduced a new paradigm in the understanding of genetic diseases, suggesting that many patients may have mutations in areas not looked at by clinical exome sequencing. While no treatments exist for brain malformations, this research opens avenues for exploring potential therapies to improve the lives of affected children and to increase support for families facing similar challenges.

Disease support organizations

Hydrocephalus Association

Hydrocephalus Association (HA) is the nation’s largest and most widely respected organization dedicated to hydrocephalus. It funds high-impact research, provides support and educational resources for patients and caregivers, and advocates on behalf of the hydrocephalus community on key policies and legislation.

Joubert Syndrome & Related Disorders Foundation

The Joubert Syndrome & Related Disorders Foundation is an international network of parents who share knowledge, experience, and emotional support. The foundation offers a networking list, newsletter, and a biennial conference.

Lissencephaly Foundation

Lissencephaly Foundation is a nonprofit organization that empowers families and educates communities by promoting a day of awareness, hosting family gatherings, providing family support, and providing educational material.

National Hydrocephalus Foundation

The National Hydrocephalus Foundation (NHF) is a nonprofit organization working to raise awareness and knowledge of hydrocephalus. It offers a variety of help guides, maintains a reference library, videos/CD’s on hydrocephalus, has support groups and assists others in starting an NHF support group in their area, and publishes a quarterly newsletter, Life~Line.

PMG Awareness

The PMG Awareness Organization is a nonprofit organization of families, caregivers and medical professionals who care about those with Polymicrogyria. They are committed to bringing awareness of Polymicrogyria (PMG) and to be a guiding light for those who have lost their way after being diagnosed.

Trusted sites