Genetic causes of Birth Defect

Dr Wed Sameer Majdali

Assistant Professor, department of medical genetics
University of Jeddah, Saudi Arabia.
French board certifed in Medical Genetics. Paris ,France
Fellowship in Prenatal genetics, Paris Necker Sick children Hospital Paris France
 Genetic causes of Birth Defect

Content
• Mechanism of birth defects
• Important terminologies in medical genetics
• Patterns and types of birth defect
• Etiological background
• Dysmorphology
• Clinical examples of genetic causes of birth defect
Dysmorphology
Birth defect

• Defnition:
Congenital malformations are single or multiple defects of the morphogenesis
of organs or body districts identifable at birth or during the intrauterine life.
• prevalence
Their global birth prevalence is about 2–3%.
Birth defect

• Impact
A correct identifcation of a congenital defect is the frst step in order to ofer a
helpful genetic counseling to the parental couple.
Because of their increasing life expectancy, congenital malformations represent
today a major issue in the health services for the amount of
 Birth defect
• Mechanisms
Birth defect
Mechanism

• Malformation
Multifactorial.
• Disruptions
Vascular or infectious causes.
• Deformations
Biomechanical forces.
• Sequence
• Syndrome
Genetic cause
Birth defect
• Malformations
Primary errors of morphogenesis, Usually Multifactorial.
ex congenital heart disease
• Disruptions
Secondary disruption of previously normal organ or body region.
Vascular or infectious causes. ex: amniotic bands
• Deformations
Extrinsic disturbance of development by Biomechanical forces.
ex: Uterine constrain (oligoamniosis)
• Sequence
Pattern of cascade anomalies explained by a single localized initation event with secondary defect in other organs
ex Pierr robin sequence
• Syndrome
Constellation of developmental abnormalities Genetic cause
ex: turner syndrom
• Deformations
extrinsic mechanical anomaly
Aesthetic deformations
Birth defect
• Disruptions
Secondary disruption of previously normal organ or body region.
Vascular or infectious causes.
ex: amniotic bands
Birth defect
• Dysplasia
Abnormality of the microscopic structure and/or abnormality of the
microscopic structure and/or function of a tissue,
usually having an evolutionary character of the function of a tissue,
Birth defect
• Malformation
Primary errors of morphogenesis, Usually Multifactorial.
ex congenital heart disease
Birth defect
• Malformation
 Major:  Minor:
▪ With a medical or psychological consequence ▪ No medical consequences
▪ 1 in 30 children (3%) ▪ 1 in 8 children (15%)
▪ Many malformations have a multifactorial etiology ▪ Can be very useful to guide the diagnosis
▪ In 10% of cases: Mendelian disease or chromosomal
abnormality
▪ 25000 children / year in F
▪ Several major malformations: 1 child / 150
Birth defect
• Malformation
 Minor abnormalities of the dvpt = "dysmorphic signs"
• Dysmorphology is : Physical/morphological perticuliarities occurring during embryogenesis
• Also known in the literature as: ▪ "minor congenital anomaly“ and "informative morphogenetic
variant"
• In general no vital or functional consequences – possibly aesthetic or psychological problem
▪ If Isolated: no meaning
▪If Associates: very informative, even characteristic
• 70%: face & hands
Birth defect
• Malformation
 Minor abnormalities = "dysmorphic signs“
Examples
▪ Epicanthus
▪ Preauricular appendix
▪ Preauricular fstula
▪ Supernumerary nipple
▪ Single transverse palmar fold
▪ Clinodactyly
▪ Partial cutaneous syndactyly II-III of the toes
Indicator
to evoke/afrm the prenatal origin of a condition of unclear etiology
Index
to suspect/diagnose, in a given context or combination, a"XYZ" syndrome
Petterns of birth defect
• Association
• Sequence
• Syndrome
Petterns of birth defect
• Association
Cluster of concomitant non-incidental abnormalities with no obvious
causal link (except chronology)

Ex ; VACTERL association
▪ Vertebral
▪ Anal atresia
▪ Cardiac
▪ TracheoEsophageal fstula
▪ Renal defects
▪ Limb defects
Petterns of birth defect

• Sequence
Complex damage secondary to an isolated anomaly

Ex Pierr Robin Sequence

Petterns of birth defect
• Sequence
Pierr Robin Sequence
It is a rare congenital birth defect
characterized by an underdeveloped jaw,
backward displacement of the tongue
and upper airway obstruction.
Petterns of birth defect
• Syndrome
Recognaizable patterns of anomalies tht are pathogenetically related.

Ex Trisomy 13, Fetal acohol

The 3 rules of dysmorphology

• No malformation is pathognomonic of a syndrome

• No malformation is constant in a syndrome
• As a rule, the presence of an unexpected malformation
does not allow to exclude a given syndrome
Birth defect
Etiologic classifcation of congenital malformations

Primary (genetic)  Secondary (environmental)

 Biologic agents
 Chromosomal abnormalities  Physical agents
 Monogenic Point mutations:  Vascular disruptions
 Polygenic  Mechanical causes
Birth defect
Etiologic classifcation of congenital malformations

Primary (genetic)
 Chromosomal abnormalities
Numeric: Polyploidy; Polysomy; Monosomy
Structural: Deletions; Duplications; Insertions;
Translocations •
 Monogenic Point mutations:
Dynamic mutations (Triplet amplifcation) Epigenetic
regulation: Imprinting defects; Uniparental disomy •
 Polygenic
Birth defect
Etiologic classifcation of congenital malformations
Secondary (environmental)
 Biologic agents
Viruses: Cytomegalovirus; Rubella; Herpes
Bacteria : Treponema pallidum
Parasites : Toxoplasma gondi
 Chemical agents
Drugs: Anticonvulsants; Antibiotics Abuse substances: Alcohol; Smoke;
Cocaine
 Metabolic conditions
Hyperglycemia, hyperinsulinemia Hyperphenylalaninemia
 Physical agents:Ionizing radiations
 Vascular disruptions
 Mechanical causes (deformations): Twinning; Oligohydramnios;
Uterine malformation
Birth defect
Etiologic classifcation of congenital malformations
Primary (genetic)
 Chromosomal abnormalities
Numeric: Polyploidy; Polysomy; Monosomy
Structural: Deletions; Duplications; Insertions;
Translocations •
 Monogenic Point mutations:
Dynamic mutations (Triplet amplifcation) Epigenetic
regulation: Imprinting defects; Uniparental disomy •
 Polygenic
Secondary (environmental)
 Biologic agents
Viruses: Cytomegalovirus; Rubella; Herpes
Bacteria : Treponema pallidum
Parasites : Toxoplasma gondi
 Chemical agents
Drugs: Anticonvulsants; Antibiotics Abuse substances:
Alcohol; Smoke; Cocaine
 Metabolic conditions
Hyperglycemia, hyperinsulinemia Hyperphenylalaninemia
 Physical agents:Ionizing radiations
 Vascular disruptions
 Mechanical causes (deformations): Twinning;
Oligohydramnios; Uterine malformation
Birth defect
Etiologic classifcation of congenital malformations

Primary (genetic)

 Contiguous gene syndrome  A single gene

Malformations Malformations
(usually several organs) Single organs
Multiple organs
Primary (genetic)
1.Contiguous gene syndrome

• Down Syndrome
Primary (genetic)
1.Contiguous gene syndrome
Primary (genetic)
1.Contiguous gene syndrome
Primary (genetic)
2.A single gene may result in multiple malformations

CHARG Syndrome
• CHD7 gene
• Major criteria ‘C's of
Coloboma,
Choanal atresia
hypoplastic semicircular Canals.
Primary (genetic)
2.A single gene may result in multiple malformations
CHARG Syndrome
• CHD7 belongs to the chromodomain helicase DNA binding (CHD)
family
• Fonctions: methylated histone binding DNA binding transcriptional
regulation cell cycle regulation chromatin remodeling
• Expression is widespread and high early in development, with
progressive restriction in CHARGE-relevant tissues.
• To understand the pathogenesis of CHARGE syndrome will be
discovering regulatory targets of CHD
Primary (genetic)
2.A single gene may result in malformation of a single organ
Lissencephaly
is a group of disorders that is characterized by
an abnormally smooth surface of the cerebral
cortex.

The frst gene identifed to cause lissencephaly

was LIS1 Other genes: DCX; TUBA1A; RELN,
VLDLR, and ARX A
 References

• Smith’s Recognizable patterns of human malformation.

Introduction.
• Thompson & Thompson Genetics in Medicine chapter 14
• Emery and Rimoin's Principles and Practice of Medical Genetics
and Genomics, 7th ed.
• (French book) Genetique medicale DFGSM2-3 , chapter13