Family History: A Guide for Neurologists in the Age

of Genomic Medicine
Jodie M. Vento, MGC, CGC

The field of neurogenetics has expanded dramatically over recent years. Neurogenetics has
developed from a distinct subspecialty within neurology to something that transcends most
of the common presenting conditions for neurologists. The importance of understanding the
genetic contribution to conditions like epilepsy, neurodevelopmental disorders, and
metabolic diseases has become very evident in neurology. In the era of personalized
medicine and genomic testing, we have just begun to understand how genetic factors
contribute to the development of disease, influence its natural history and severity, and
determine its response to therapy. Genetic risk analysis and interpretation have become
central components for the modern clinical assessment, and a comprehensive family
history analysis is essential for neurologists. The benefits of collecting and updating a
detailed pedigree are important for diagnostic guidance, risk counseling, and test
interpretation. A review of genetic inheritance patterns, pedigree construction, and factors
that influence disease presentation is outlined for the application in neurology practice.
Semin Pediatr Neurol 19:160-166 C 2012 Elsevier Inc. All rights reserved.

Introduction Health care professionals have long recognized the

There is a growing initiative to promote collection of family
health history information in settings outside of the
genetics clinic. Family history awareness programs have
been aimed at the patient population, and there is an
increasing desire for patients and families to learn about
their own genetic make-up and empower their health care
decisions. Specialty clinics, such as pediatric neurology
clinics, are rich resources for family history collection.
Neurology departments differ from other specialty clinics
because many neurologic disorders have a genetic etiology
and these patients may be first identified by a neurologist.
While referrals to genetics clinics are utilized in some cases,
many neurologists are initiating genetic and metabolic
testings. The value of integrating guidelines on genetic
diagnostic testing has been emphasized in many neurology
journals. As neurologists are given new tools for their
unknown diagnoses, such as the chromosome microarray,
next-generation sequencing, and genomic technologies,
there needs to be a precedent to appropriately utilize the
family history to guide and interpret these studies.
From the Division of Child Neurology, Children’s Hospital of Pittsburgh of
UPMC, Pittsburgh, PA.
Address reprint requests to Jodie M. Vento, MGC, CGC, Children’s
Hospital of Pittsburgh of UPMC, Division of Child Neurology, 4401
Penn Avenue, Pittsburgh, PA 15224. E-mail: Jodie.Vento@chp.edu
benefits of incorporating one’s family history into their
medical care. Family history can be utilized as a cost-
effective means for genetic diagnosis by aiding in the
identification of patterns of inheritance, establishing rap-
port with the patient and family, distinguishing genetic risk
factors from other environmental risk factors, and deter-
mining medical surveillance for at-risk relatives.1 In the
new era of genomic medicine, family history remains
paramount to the accurate interpretation of complicated
testing results. New genomic testing technologies have
revealed novel disease-causing genes, new syndromes,
and different presentations of previously described syn-
dromes. Our understanding of the phenotypic spectrum
of many diseases will continue to broaden. Family history
would be an essential component in our understanding of
genetic variation and disease presentation.
Family History Collection in
Neurology
While the collection of a comprehensive 3-generation
pedigree is ideal, the potential time burden may make this
impractical for the busy neurologist. The clinician must
determine the level of detail to collect based on the patient’s
specific symptoms and circumstances. Pedigrees are espe-
cially useful because they utilize standard symbols and

160 1071-9091/12/$-see front matter & 2012 Elsevier Inc. All rights reserved.
doi:10.1016/j.spen.2012.09.002
Family history: A guide for neurologists 161

Figure 1 Standardized pedigree symbols and example pedigree.

terminology to represent a large amount of information example, ‘‘The patient has one sister, two brothers, multiple
within a single diagram. Standardized pedigree nomencla- paternal cousins, and no maternal cousins. The family history
ture2 and an example pedigree are demonstrated in is unremarkable for seizures, intellectual disability, congenital
Figure 1. The clinician recording the information should
focus on several key elements, shown in Table 1. However, Table 1 Key Family History Elements in Child Neurology
specific inquiries may be warranted depending on the Family Members
presenting condition. For example, if a child presents with First-degree relatives (parents, children, and siblings)
a single febrile seizure and a parent has a history of Second-degree relatives (half-siblings, grandparents,
epilepsy, it is important to know the age of onset, cognition aunts, uncles, and grandchildren)
level, type of seizures (including febrile and afebrile), and Third-degree relatives (cousins)
the etiology, if known.
Conditions
One of the difficulties in family history collection is the Seizures and spells
subjective variability of the information provided by the Mental retardation or intellectual disability
historian. Family myths, biases, and misunderstandings can Learning disability, speech and language disorders
lead to incorrect information. Whenever possible, it is helpful Headache and migraine
to verify key medical information with further probing Psychiatric conditions
questions or review of pertinent medical records. Documenta- Deafness and blindness
tion of the family history is critical to its integration in the Neuromuscular issues
long-term health care of a patient. Many times clinicians Stroke (especially early-onset or without environmental
would note an ‘‘unremarkable family history’’. While this is risk factors or both)
typically helpful, it may be misleading. There are several Birth defects and congenital anomalies
Pregnancy losses
alternate explanations for a seemingly unremarkable family
Sudden or unexpected death
history, including poor historian recall or report of misinfor-
mation, small family size, failure of clinician to obtain full 3- History
generation pedigree, reduced penetrance, sex-limited inheri- Age of onset
tance, and misattributed family relationships. Documentation Age and cause of death
of a full pedigree can aid in distinguishing the above- Ancestral origins
mentioned factors. In the least, it is helpful to state what Consanguinity
Pregnancy outcomes
questions were asked about which family members. For
162 J.M. Vento

anomalies, and stroke.’’ Many electronic medical records
systems have created a centralized place to store family history
data, and a pedigree allows for a fast, effective visual record.
Because many patients with potential neurogenetic conditions
may follow up with a neurologist for many years, frequent
visits allow for the collection of an evolving and dynamic
family history over time, and pedigrees are easily updated.
Many families have become accustomed to being asked
about their family health history, but others may be more
reluctant to share certain information. In the pediatric
setting, it can seem far-reaching to ask about distant
relatives’ pregnancies or cancer histories to some families.
Introducing the purpose of the family history can help to
build rapport, elicit additional information, and lay the
groundwork for the interview. A simple statement like
‘‘I am going to ask you some questions about the medical
and developmental histories of your family members. This
information can help to guide the medical treatment of
your child.’’ can be helpful. Use of common language when
eliciting specific information can aid in decreasing mis-
understanding. For example, asking about neuromuscular
conditions may not be as readily understood as asking
about anyone with weakness or with a need for a wheel-
chair. Leading questions can sometimes bias responses.
Saying ‘‘no medical issues for your nieces or nephews,
correct?’’ may lead to a different response than ‘‘do any of
your nieces or nephews have any medical concerns?’’
Additionally, it can be helpful to clarify that you are asking
about all medical conditions, including those in the past.
Be sensitive to cultural differences and issues, especially
when inquiring about parents who are related by blood.
Family History Analysis
Mendelian Inheritance Patterns
Risk analysis and inheritance pattern recognition are often
the key goals of family history collection. Genetic ‘‘red
flags’’ are indicators from the personal and family history
that there might be an increased genetic risk in an
individual or family. The most obvious red flag is when
there are a large number of affected relatives with the same
(or similar) condition that share a close degree of relation-
ship. While most commonly this indicates a genetic
condition, consideration should also be made for the
environmental factors that may be shared within families.
Genetic red flags are outlined in Table 2. Knowledge of
common Mendelian inheritance patterns can aid in

Table 2 Family History Genetic Red Flags11,12

Red Flag Explanation

Family history of multiple affected family members Indicates increased risk, whether through genetic, or environmental risk
with the same or related disorders factors, or both
eg, Epilepsy in two siblings and a parent

Earlier age at onset of disease than expected May be due to a genetic predisposition that makes an individual more
susceptible to environmental exposures
eg, Multiple strokes in a teenager

Condition in the less-often-affected sex May occur because of a genetic predisposition that overrides other
hormonal, developmental, and environmental factors
eg, A female with autistic regression

Disease in the absence of known risk factors Genetic predisposition may lead to a particular disorder without any known
environmental factors
eg, Periventricular leukomalacia in the absence of prematurity, or infection,
or both

Ethnic predisposition to certain genetic disorders Some genetic disorders are more common in certain ancestral groups
eg, Maple Syrup urine disease (MSUD) in the Pennsylvania Mennonite
population

Close biologic relationship between any parents Relatives are more likely to share the same genetic alterations; thus,
(ie, consanguinity) offspring from a consanguineous couple are at a higher risk for having an
autosomal recessive disease
eg, A child of a consanguineous couple with a Krabbe disease

Multiple congenital anomalies Two or more congenital anomalies in an individual are more likely to be
caused by a genetic syndrome
eg, A child with a congenital heart defect and lissencephaly who has Miller-
Dieker syndrome

Neurodevelopmental delay (especially with Developmental delay in the pediatric age group carries an elevated risk for
regression) genetic disorders. Any loss of skills should increase this suspicion
eg, A 2-year-old female who losses purposely movement of her hands who
has Rett syndrome
Family history: A guide for neurologists
Figure 2 Example pedigree inheritance patterns.
determining an approach to diagnostic testing. Addition-
ally, this can help to interpret genetic testing results and
identify family members who might be at risk for neuro-
genetic conditions. Key inheritance patterns are outlined
later and in Figure 2.
Autosomal Dominant (AD) Inheritance
AD conditions are those that only require 1 mutant gene
(allele) to manifest disease. The mutated gene copy
‘‘dominates’’ the normal gene product. In reviewing family
history information, one would often note equally affected
males and females, multiple affected generations, and male-
to-male transmission. For an individual affected by an
AD condition, each offspring would inherit either the
mutant allele or the normal allele. As such, the offspring
of someone with an AD condition has a 50% recurrence
163
risk. Nearly half of all single-gene disorders are inherited in
an AD fashion.3 Many of the AD conditions can have
variability in disease manifestation. This can make identi-
fication through pedigree analysis more challenging and
prognostic counseling more convoluted. Additionally, many
AD conditions have a high frequency of new mutations, so
family history may be unremarkable. For example, nearly
half of the individuals affected with neurofibromatosis, type
1 have de novo mutations that were not inherited from
a parent.4 Two of the sodium channel genes, SCN1A and
SCN1B, are involved with varying AD epilepsy phenotypes.
The spectrum of phenotypes associated with the sodium
channelopathies includes simple febrile seizures, general-
ized or genetic epilepsy with febrile seizures plus (GEFSþ),
and severe myoclonic epilepsy of infancy (SMEI) or Dravet
syndrome. Many children with the more severe phenotype
of Dravet syndrome have an identifiable de novo (new)
164
mutation in SCN1A. When a child is identified to have an
AD condition and parental testing is negative, it is
considered a de novo mutation. This differs from children
that may present with the milder GEFSþ and an identifi-
able SCN1B mutation. SCN1B mutations are also AD, but
typically not de novo. As such, family history can help to
guide appropriate diagnostic testing and recurrence risk
counseling.
Autosomal Recessive (AR) Inheritance
AR conditions are those conditions that require 2 mutated
alleles to manifest disease. Most of the time, carriers (those
with only 1 mutated allele) do not manifest disease or may
only have mild symptoms. All humans carry several AR
mutations, but the chance that an individual would have an
offspring with an AR condition depends on the carrier
status of his or her partner for the same conditions. Family
history would often be unremarkable, unless there is an
affected sibling or consanguinity present, and there is an
equal risk for both males and females to be affected. If
a child is diagnosed with an AR condition, it is important to
offer targeted testing to parents to confirm carrier status
and identify risks to any siblings. Two carriers of an AR
condition have a 25% chance of having an affected
offspring, a 50% chance of having a carrier offspring, and
a 25% chance of having an unaffected, noncarrier offspring
with each pregnancy. Many neurometabolic conditions,
such as Krabbe disease, metachromatic leukodystrophy,
and Tay-Sachs, are inherited in an AR fashion.
X-linked Inheritance
Females have 2 X chromosomes, and males have an X
chromosome and a Y chromosome. X-linked inheritance is
caused by a mutated X chromosome. Females only require
1 working copy of the X chromosome in each cell in their
body and randomly inactivate the other copy of the X
chromosome. This is a protective mechanism in females,
and 1 of the key characteristics of X-linked inheritance is
a family history with only males affected (or males affected
more severely than females) and with no male-to-male
transmission. The concept of dominant and recessive
X-linked inheritance can be blurry due to X-inactivation
(explained later). Many diseases that were previously
described as X-linked recessive disorders can have females
who present with milder symptoms. For example, Duchenne
muscular dystrophy was historically believed to affect only
males. Now, we know that some carrier females may have
muscle weakness, myalgia, and cardiac complications.5
These family histories will often present with disease that
appear to ‘‘skip’’ generations. Some X-linked disorders are
typically lethal in males and would cause symptoms only in
females (eg, Aicardi syndrome). These are often referred to
as X-linked dominant disorders. One of the urea cycle
disorders, ornithine transcarbamylase deficiency (OTC), is
caused by alterations in the OTC gene located on the X
chromosome. OTC deficiency is often more severe in males
J.M. Vento
who rapidly develop hyperammonemic coma in the new-
born period, whereas only approximately 15% of carrier
females would develop symptoms ranging from behavioral
and learning disabilities to protein intolerance, cyclical
vomiting, and hyperammonemic crises during their
lifetime.6
Nontraditional Inheritance Patterns
Mitochondrial Inheritance
Mitochondrial diseases are a genetically and clinically
diverse group of disorders that arise as a result of
dysfunction of the mitochondria, which are responsible
for making most of a cell’s energy in the form of adenosine
triphosphate. Some of the commonly observed symptoms
associated with mitochondrial disease can be classified into
discrete clinical syndromes; however, the presentation and
severity of these conditions may have wide variation,
creating challenges in diagnosis and recurrence risk coun-
seling. Mitochondrial disorders can be caused by altera-
tions in nuclear DNA (nDNA) or mitochondrial DNA
(mtDNA), or both. The mtDNA and nDNA have a
symbiotic relationship that is essential for normal function-
ing of the electron transport chain and mitochondria. As
such, this group of disorders may be inherited in different
manners. The nDNA alterations are most often AD or AR
(however, X-linked genes have been identified). While not
always possible, establishing a molecular genetic diagnosis
is fundamental in providing accurate recurrence risk and
clinical prognostic counseling. If mutations are identified
in an nDNA gene that is known to be inherited in an AR
manner (SURF1 or DGUOK), siblings may be the only other
affected family members. Some of the nDNA genes can be
inherited in either an AR or AD fashion (ie, POLG1),
depending on the specific mutation(s). In this case, it is
important to offer parental testing to determine the phase
of the mutations (cis or trans) and research genotype-
phenotype correlations to accurately discuss recurrence
risks and identify other family members at risk. In POLG1,
the prognosis and associated medical implications with the
AR and AD variations can differ. Mitochondrial diseases,
caused by alterations in the mtDNA, are always maternally
inherited because ova contain mitochondria, whereas any
mitochondria in the sperm are either diluted or destroyed.
Mitochondrial encephalomyopathy with lactic acidosis and
stroke-like episodes most commonly presents with stroke-
like episodes, encephalopathy with seizures or dementia,
and myopathy during childhood. However, there can be
much intrafamilial phenotypic variability. Some individuals
may only have hearing loss or diabetes mellitus. The
difficulty in accurately predicting the clinical consequences
and inheritance of mtDNA abnormalities is due to several
complicating factors, including heteroplasmy, and the
bottleneck and threshold effects. Heteroplasmy describes
a mixture of mitochondria within 1 single cell, with some
containing mutant DNA and some containing normal DNA.
As technology improves, there is an increased ability to
detect heteroplasmy levels through both blood and tissue
Family history: A guide for neurologists
analyses. As with many genetic conditions, determining
underlying genotype may be more straightforward, whereas
predicating clinical consequences is more challenging.
While a mother with mtDNA alterations transmits mutant
mtDNA to all of her offspring, the degree of heteroplasmy
can vary from egg to egg because of the random bottleneck
effect during oogenesis. The threshold effect describes the
minimum amount of energy required by a cell, tissue, or
organ to function properly. This threshold can vary over the
course of development, during times of physiological stress
(illness), and from tissue to tissue. Some tissues require
more energy (ie, brain and muscle) than others (ie, skin)
and therefore have a lower energy threshold and tolerance
for mutant mitochondria.
Although most mtDNA point mutations are maternally
inherited, most mtDNA deletions are de novo, occurring
either in the mother’s oocyte or during embryogenesis. The 3
overlapping phenotypes associated with mtDNA deletions are
Kearns-Sayre syndrome, Pearson syndrome, and progressive
external ophthalmoplegia. Determining whether an mtDNA
deletion is inherited maternally or de novo is essential for
proper genetic counseling and medical management of family
members.
Chromosomal Inheritance
Chromosome microarray technology has revealed a chromo-
somal etiology for many children with neurodevelopmental
disorders. Chromosome microarray finds a pathogenic
deletion or duplication in 15%-20% of children tested for
autism spectrum disorder, developmental delay or intellec-
tual impairment, and congenital anomalies.7 Many micro-
deletions and microduplications may be de novo; however,
some parents have been found to harbor the same chromo-
somal aberration. Generally speaking, autosomal deletions or
duplications are inherited in an AD fashion, with a high
degree of de novo alterations. Deletions and duplications on
the X chromosome typically follow the X-linked inheritance
patterns described previously. Some of the genetic red flags
that could indicate a chromosome disorder are multiple
congenital anomalies, dysmorphic features, and multiple
miscarriages. Some children are born with unbalanced
chromosome aberrations due to a parental balanced translo-
cation. Many individuals with balanced translocations will
be asymptomatic. The specific reproductive risks to a parent
with a balanced translocation can vary depending on the size
and location of the chromosome alteration.
Multifactorial and Polygenic Disorders
Some common neurologic disorders are believed to be
multifactorial in some instances, having both genetic and
environmental contributions (eg, autism and epilepsy).
When a clear molecular etiology is not ascertained in these
conditions, genetic counseling can be difficult. We often
have to rely on empiric studies to provide recurrence risk
estimates to families. Careful, detailed evaluation of the
family history may allow for a more tailored risk estimate in
these circumstances. For example, if the male and female
offspring of a couple both have autism, and chromosomal
165
and molecular analyses have been uninformative, it would
be reasonable to provide a recurrence risk of about 25% to
the parents, whereas if the proband is the only affected
individual in a large family, empiric estimates of autism
recurrence would provide a more appropriate risk estimate
for families. As genomic technology advances, our historic
understanding of single-gene disorders will likely
expand and the interplay between polygenic and envir-
onmental factors’ influence on disease may be better
understood.
Factors Affecting Genetic Disease
Manifestation and Pedigree Interpretation
Germline Mosaicism
Once a genetic alteration is identified in a child, it is
appropriate to offer parental testing and tailored genetic
counseling. If the parents are tested and found to not be
carriers of a known genetic alteration, then it is most
typically believed to be a de novo alteration. While the risk
to the future offspring of these parents is likely very low,
it is very important to discuss the risk for germline
mosaicism. Individuals with germline mosaicism are typi-
cally asymptomatic, but may have the mutation(s) present
in some or all of their germline cells. This means that there
is a possibility of having normal parental carrier testing, but
passing the disorder on to their children. For example,
most cases of Rett syndrome are sporadic, but there have
been reports of multiple affected siblings with mothers who
had normal carrier testing for MECP2. It is suspected that
these cases arose due to maternal germline mosaicism.8 As
such, it is important to offer genetic counseling and
reproductive testing options to these families. Depending
on the condition, the risk for germline mosaicism may vary,
but is typically low.
Penetrance
Penetrance describes the possibility that a given gene
alteration would manifest in the form of a disease and is
most often associated with AD inheritance. Complete
penetrance is when clinical symptoms are present in all
individuals who have the disease-causing genetic alteration,
and reduced or incomplete penetrance describes the
condition when clinical symptoms are not always present
in individuals who have the disease-causing genetic altera-
tion. Incomplete penetrance often creates a pedigree that
looks like a generation is ‘‘skipped’’. In early-onset primary
dystonia, typically caused by a 3 basepair deletion in
TOR1A, only about 30% of individuals would ever actually
develop dystonia.9 Sometimes, however, comprehensive
molecular and clinical examination reveals minimal signs
of a particular syndrome, indicating variable expressivity of
the disease symptoms, rather than incomplete penetrance.
Variable Expressivity
Variable expressivity refers to the variation in severity of
disease manifestation in different people with the same
genetic condition. Both interfamilial and intrafamilial
166
variabilities have been demonstrated in a number of genetic
syndromes. Variations between families can be due to
different mutations at the same disease locus, whereas
variation within families is most likely due to other
modifier genes, environmental factors, or other stochastic
events. For example, interfamilial variability can be noted
in cerebral AD arteriopathy with subcortical infarcts and
leukoencephalopathy. While one family member may present
with cerebellar ataxia, another may have dementia or psy-
chiatric disturbance, or both as their presenting feature.10
Skewed X-inactivation
X-inactivation is the phenomenon in females by which one
X chromosome is randomly inactivated in each somatic cell
as a method of dosage compensation. Typically, this occurs
in a random pattern with about 50% paternal and 50%
maternal X chromosomes inactivated. This becomes impor-
tant when a carrier female of an X-linked recessive
condition demonstrates skewed X-inactivation. In cases
where this process leads to the skewed inactivation of more
X chromosomes containing the affected gene, there can be
a milder phenotype. Transversely, if more of the unaffected X
chromosome is inactivated, there can be more severe symp-
toms. This phenomenon also explains the clinical variability
in females with X-linked diseases. Females with mutations in
the X-linked PDHA gene associated with pyruvate dehydro-
genase complex deficiency can demonstrate a spectrum of
disease severity, depending on their X-inactivation pattern.
Anticipation
Anticipation describes the tendency, in certain genetic
disorders, for individuals in successive generations to
present with more severe disease manifestations (often at
an earlier age of onset) than expected. This process is
typically observed in genetic syndromes that are the result
of a trinucleotide repeat mutation or expansion, such as
myotonic dystrophy type 1 and fragile X syndrome.
Anticipation in fragile X syndrome may not happen with
every generation, as many families transmit premutation
alleles for generations with little or no presentation of
clinical symptoms until a trinucleotide repeat expansion
leads to the full mutation, resulting in an affected indivi-
dual. In some conditions, anticipation is dependent on the
parent who transmits the altered gene. For example,
paternal anticipation is often demonstrated in Huntington
disease (HD). When a child is diagnosed with juvenile HD,
it is usually inherited from an affected father. Mothers can
still pass on HD to successive generations, but anticipation
is generally not noted.
J.M. Vento
Conclusions
Family history collection and interpretation remains an
essential tool for neurologists. Determining how and when
to approach genetic testing is greatly influenced by one’s
family health history. With new, large genetic testing panels
and genomic-based analyses, family history is crucial to
dissecting the abundance of genetic data and variation that
is discovered. Many laboratories will request parental
samples and family history to help distinguish the patho-
genicity of variants of uncertain significance. Collaboration
with genetics professionals can help to provide risk assess-
ment and targeted counseling to families and patients.
Recording a detailed family that is available for modification
over time allows for improved patient care, especially with
the influx of genomic information that is becoming central
to the personalized medicine revolution.
References
1. Bennett RL: The Practical Guide to the Genetic Family History. Wiley-
Blackwell, New York, NY, 2010
2. Bennett RL, K. SF, Resta RG, et al: Standardized pedigree nomen-
clature: update and assessment of the recommendations of the
National Society of Genetic Counselors. J Genet Couns 17:424-433,
2008
3. National Coalition for Health Professional Education in Genetics
(NCHPEG). Genetic Red Flags, 2008. Available at: /http://www.
nchpeg.org/S. Accessed August 10, 2012.
4. Whelan AJ, Ball S, Best L, et al: Genetic red flags: clues to thinking
genetically in primary care practice. Prim Care 31:497-508, 2004
5. Nussbaum RL, McInnes RR, Willard HF: Thompson and Thompson:
Genetics in Medicine, 7th ed. Philadelphia, PA, Elsevier, 2007
6. Jett K, Friedman JM: Clinical and genetic aspects of neurofibromatosis
1. Gen Med 12:1-11, 2010
7. Hoogerwaard EM, van der Wouw PA, Wilde AA, et al: Cardiac
involvement in carriers of Duchenne and Becker muscular dystrophy.
Neuromuscul Disord 9:347-351, 1999
8. Gyato K, Wray J, Huang ZJ, et al: Metabolic and neuropsychological
phenotype in women heterozygous for ornithine transcarbamylase
deficiency. Ann Neurol 55:80-86, 2004.
9. Miller DT, Adam MP, Aradhya S, et al: Consensus statement:
chromosomal microarray is a first-tier clinical diagnostic test for
individuals with developmental disabilities or congenital anomalies.
Am J Hum Genet 86:749-764, 2010
10. Venâncio M, Santos M, Pereira SA, et al: An explanation for another
familial case of Rett syndrome: maternal germline mosaicism. Eur J
Hum Genet 15:902-904, 2007
11. Kostić VS, Svetel M, Kabakci K, et al: Intrafamilial phenotypic and
genetic heterogeneity of dystonia. J Neurol Sci 250:92-96, 2006
12. Vedeler C, Bindoff L: A family with atypical CADASIL. J Neurol
258:1888-1889, 2011