Multiple Sclerosis Family Study - Study to investigate whether rare gene mutations cause Multiple Sclerosis (MS) in ten Dutch families with multiple MS patients

Multiple sclerosis (MS) is a chronic inflammatory and degenerative disease of
the central nervous system (CNS) with a highly heterogeneous course of disease
progression. In the CNS, the neuronal extensions that transmit brain signals,
are enveloped in myelin sheets to properly conduct the electrical activity. The
myelin sheets are created and maintained by oligodendrocytes. In MS,
inflammations harm the blood brain barrier, activate the immune response and
ultimately cause demyelination (Franklin & Ffrench-Constant, 2008). This leads
to progressive neurodegeneration (Trapp & Nave, 2008). MS is caused by a
complex interplay of genetic and environmental factors, but the causes of this
disease are not yet fully understood (Hauser & Oksenberg, 2006; Lucchinetti et
al., 2000).

Most patients with MS initially experience periods of weeks to months with more
or less extensive neurological symptoms and impairments (relapses), followed by
periods in which these symptoms/impairments disappear partially or completely;
this is called the relapsing-remitting form of MS (RRMS). In the absence of
treatment, more than 50% of patients with RRMS will develop progressive
disability after approximately 15 years (secondary progressive MS, SPMS)
(Rovira, Auger, & Alonso, 2013). Other subclasses for MS include the primary
progressive form of MS (PPMS) where patients experience severe
neurodegeneration without the typical relapses, and Progressive Relapsing MS
(PRMS), a subtype that is related to PPMS, but with distinct acute relapses
that may or may not include recovery.

Currently, thirteen DMTs are approved and registered for the treatment of RRMS,
with many new treatments currently in clinical testing, including treatment
options for the PP form of MS. A strong variety in responses to MS therapies
reflect the differences in underlying pathology. The heterogeneity in MS is
linked to both genetic and environmental factors (Lucchinetti et al., 2000).
While current MS treatments are able to reduce the (increase in) clinical
disability, particularly when appropriate treatment occurs during the early
stages of the disease, there are to date no curative therapies available to
relieve the symptoms. It is therefore important to (1) improve classification
of MS disease subtype in order to more effectively provide treatment to the
patients and (2) improve the biological understanding of MS to provide new
treatment options, with the aim to develop curative therapies.

In several neurological disorders, identification of de novo/rare mutations has
provided insight into the molecular mechanisms, i.e. for autism spectrum
disorders (Sanders et al., 2012), schizophrenia (Xu et al., 2011), language
impairments (Fisher & Scharff, 2009) and intellectual disability (Mitra, Dodge,
Van Ness, Sokeye, & Van Ness, 2017). Recent advances in WES, are identifying
the genetic basis of disease for 25-40% of patients (Sawyer et al., 2016). To
identify de novo/rare mutations, research is focused on families with multiple
affected family members across generations. These families are more likely to
have de novo/rare mutations with strong effects, as opposed to more common
variants with a small effect size. De novo/rare mutations with a strong impact
on health were generally not preserved during evolution. Identification of rare
mutations in familial cases provides researchers strong leads towards the genes
involved in a disease. In non-familial cases of complex diseases, generally a
large number of genetic variants with weak effect sizes contribute to the
development of a disease (Acuna-Hidalgo, Veltman, & Hoischen, 2016; O*Roak et
al., 2011; Vissers et al., 2010). In familial cases the related patients often
have similar age of onset and disease severity (Korn, 2008; Trapp & Nave,
2008). For MS, few rare mutations have been identified, and additional studies
using WES are needed to understand the disease mechanism (Trapp & Nave, 2008;
Wang et al., 2016).

In recent years, WES has become a popular method to identify rare genetic
variants that are causative of diseases, and to subsequently improve the
understanding of disease mechanisms and to help with diagnosis (Bamshad et al.,
2011). In contrast to GWAS studies that focus on sequencing common variants in
large sample sizes, WES is a new technique used to decipher the protein coding
parts of the DNA and to search for de novo/rare variants not found in the
general population. WES is more cost effective than Whole Genome Sequencing
(WGS), and shows a lot of promise in identifying previously illusive genes
involved in complex diseases like MS (Sawyer et al., 2016).

Increased familial risks in multiple sclerosis (MS) range from 300-fold for
monozygotic twins to 20-40-fold for biological first-degree relatives,
suggesting a genetic influence (Sadovnick, Ebers, Dyment, & Risch, 1996).
Familial cases of MS are thus relatively common and related patients often have
similar age of onset and disease severity (Korn, 2008). Furthermore, the
severity of genetic predisposition to get MS is related to an early onset of
the disease (Sadovnick, Yee, Ebers, & Risch, 1998; Trapp & Nave, 2008).
Identifying genes that are causative of familial clustering of MS and relating
these specific mutations to the disease phenotype will enhance our overall
understanding of the disease. The specific information could be used in future
personalized diagnostics and treatments. One such mutation has recently been
found using WES in the gene NR1H3, a nuclear receptor involved in inflammation
and immunity (Wang et al., 2016). Another familial sequencing study has
identified a rare mutation in the CYP27B1 gene is involved with the vitamin D
pathology implied in MS (Ramagopalan et al., 2011). Likewise, a similar study
has identified a variant in the TYK2 gene across four generations in one family
affecting a subset of MS patients (Dyment et al., 2012). Taken together,
identification of rare mutations in familial MS can highly improve the
understanding of the underlying pathology. This will improve classification of
the disease subtype and provide opportunities to develop novel therapies for
patients with MS.

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Our primary objective is to identify de novo/rare mutations causative of MS
using WES in members of multi-incident families. Our secondary objective is to
describe phenotypes per family using questionnaires and semi-structured
interviews with family members. Using literature review, we will aim to explain
the relationship between phenotype and the genetic/biological findings.

Patient-control study within families

For the genetic analysis, the patients will be asked for a blood sample, which
will be collected during a home visit by certified personnel only. The patients
will also be asked to fill in two questionnaires to gain insight into their
disease status and history. Furthermore, to gain detailed information about
family history in terms of environmental factors, the MS patients and a
matching number of control family members will be asked for a 30 minute
semi-structured interview per patient/control subject. A potential risk is that
the patients are confronted with heritability of their disease and reflect on
their family situation regarding MS.