GeNeViSTA

Fetal Dysmorphology: An Indispensable Tool for Synthesis of Perinatal Diagnosis

Shagun Aggarwal Department of , Nizam’s Institute of Medical Sciences, Hyderabad & Centre for DNA Fingerprinting and Diagnostics, Hyderabad

Email: [email protected]

Introduction for pregnancy management as it aids in accurate prognostication and communicating the possibility of and other co-morbidities in Dysmorphology is the science (and art!) of studying such children, helps in decision-making regarding abnormal form, with special emphasis on subtle termination or continuation of pregnancy, facili- ndings which provide clue to an underlying diag- tates appropriate postnatal management and also nosis, mostly a genetic syndrome. It has been the provides recurrence risk estimates for subsequent prime tool of the geneticist enabling a syndromic conceptions. In the postnatal scenario, such a diag- diagnosis on basis of patient’s gestalt with ndings nosis facilitates emotional closure, recurrence risk like a white forelock, heterochromia iridis, broad counseling and early, denitive prenatal diagnosis thumb, asymmetric crying facies and many other in subsequent pregnancies. subtle features acting as decisive tools in the ge- Any morphological or growth abnormality in the netics clinic. Most individuals with dysmorphism fetal life can be an isolated abnormality of multi- are affected with genetic syndromes, which can factorial origin, the consequence of environmental be due to chromosomal abnormalities, copy num- etiologies like a teratogenic insult, intrauterine fac- ber variations or single defects. However, tors, maternal illness, etc. or a component of a various environmental factors can also lead to genetic syndrome. In such a scenario, it is impor- dysmorphism, many times mimicking specic ge- tant to be aware of these possibilities, and perform netic syndromes due to involvement of a common a complete dysmorphological evaluation with an biological pathway. A dysmorphological evaluation aim to distinguish between these different situa- typically involves a head to toe examination look- tions with varied prognosis and recurrence risks. ing for malformations, and minor features showing Figure 1 shows some common fetal abnormalities deviation from the expected norm as per sex, and respective etiologies. age, family background and ethnicity. This often forms the rst and most crucial step in establishing a genetic diagnosis and is subsequently followed Setting of fetal dysmorphology by relevant genetic testing for conrmation. In There are two main settings where syndromic di- the era of next generation sequencing when the agnosis in the fetus is a possibility and should be rate of gene discovery has surpassed the clini- actively looked for: cal recognition of a new genetic syndrome and reverse phenotyping has become commonplace, a. Abnormal antenatal ultrasound. dysmorphology still remains an important tool in the hands of an experienced geneticist. b. Postmortem evaluation of an unexplained fetal demise or morphologically abnormal fetus. Although as a discipline dysmorphology evolved in the paediatrics setting, it can be extended to Abnormal antenatal ultrasound: Abnormal- the fetal life to enable the diagnosis of a genetic ities• on antenatal ultrasound can be found in syndrome in the fetus. The recognition of a genetic 5-10% of pregnancies. These can vary from growth syndrome in particular, has important implications abnormalities, major or minor malformations, soft

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Fetal abnormality Acquired etiologies Genetic etiologies

Naso-maxillary • Fetal warfarin syndrome • Brachytelephalangic hypoplasia/Binder • deficiency chondrodysplasia punctata facies • Keutel syndrome • Vitamin K metabolism defects

Talipes- • Oligohydramnios • Chromosomal disorders: sex equinovarus • Uterine malformations chromosome • Multiple pregnancy • Neuromuscular disorders • Skeletal dysplasias Cleft lip • Multifactorial • Isolated Mendelian* • Fetal hydantoin syndrome • Syndromic- chromosomal disorders, copy number abnormalities or Mendelian disorders#

Ventriculomegaly • Fetal infections • Isolated Mendelian* • Intracranial hemorrhage • Syndromic- Chromosomal disorders • Associated with neural • Copy number abnormalities tube defect (multifactorial) • Mendelian disorders#

Hydrops fetalis • Blood group antigen • Chromosomal disorders: Turner isoimmunisation syndrome, • Fetal infections esp. • Mendelian disorders#: Noonan Parvovirus syndrome, primary lymphatic • Hypothyroidism dysplasias, alpha thalassemia, • Congenital heart block, lysosomal storage disorders, others fetal arrhythmias • Cardiac defects Neural tube defect • Maternal • Isolated Mendelian* • Maternal hyperthermia • Syndromic- Chromosomal, • Folate deficiency Mendelian# eg. Meckel-Gruber syndrome, Spondylocostal dysostosis

*Isolated Mendelian: Isolated defect due to in single gene #Syndromic Mendelian disorder: A spectrum of multiple defects arising due to mutation in single gene

Figure 1 Common fetal abnormalities and their etiologies. markers and liquor or placental abnormalities. along with relevant images to enable recognition of At least 10-30% of prenatally detected malforma- dysmorphic facies, recognize the pattern of abnor- tions are due to a genetic etiology (Beke et al., malities and elicit a detailed family history, which 2005). This gure is much higher for specic ab- would help in synthesis of a syndromic diagnosis. normalities like omphalocele, holoprosencephaly The advent of 3D ultrasound technology provides and cystic hygroma where 50-90% cases can be opportunity for facial dysmorphism recognition, attributed to genetic abnormalities involving the and can be used as an adjunct to the conventional chromosomes. In each of these scenarios, the 2D ultrasonography. antenatal ultrasonography should be performed by a fetal medicine specialist with a dysmorphol- Postmortem evaluation/ Fetal autopsy: ogy or clinical genetics knowledge. Alternatively, Post-mortem• evaluation is an important modal- a clinical geneticist consultation should be sought, ity for establishing the cause of unexplained fetal

Genetic Clinics 2017 | April - June | Vol 10 | Issue 2 12 GeNeViSTA deaths as well as a medically terminated mor- opment. Maternal drug use especially antiepileptic phologically abnormal fetus. At least 15-30% of drugs, derivatives, ACE inhibitors and stillbirths are reported to be due to genetic causes some rarer drugs like retinoic acid derivatives, (fleddy et al., 2012). Besides the histopatholog- thalidomide, etc. needs to be ascertained as these ical examination of the placenta which provides are known to be potent fetal teratogens. Some evidence of acquired insults like utero-placental of these can result in fetal malformations which insufficiency and perinatal infections, dysmorpho- mimic genetic disorders involving defects in the logical evaluation by a geneticist or perinatal common biological pathway. An example is fetal pathologist with expertise in dysmorphology is es- warfarin syndrome, arising due to exposure to war- sential for syndrome recognition. Various studies farin in the rst half of pregnancy. Warfarin inhibits indicate that autopsy provides additional ndings the activity of Vitamin K, and its fetal effects are or modies the antenatal diagnosis in 20-50% cases similar to a brachytelephalangic (flodriguez et al., 2014). Antenatal series have also chondrodysplasia punctata which is caused by a shown that at least 50% syndromic diagnoses are mutation in the ARSE gene, important for Vitamin K possible only after an autopsy (Stoll et al., 2003). metabolism in the body. Hence, all cases with abnormal ultrasound ndings Family history: A three-generation family should undergo a post-mortem evaluation. pedigree• forms the cornerstone of the family his- tory ascertainment. This can provide important Practical approach to fetal information like consanguinity, which increases the dysmorphology risk of autosomal recessive disorders; previous fetus or child with similar or overlapping pheno- The evaluation of the fetus in-utero and/or post- type; other family members with pregnancy losses, mortem for syndrome recognition involves the infertility or abnormal offspring indicating possi- following steps (depicted in gure 2): bility of a chromosomal rearrangement or single gene etiology; and at times a parent with milder Antenatal and medical history manifestation of the same condition as the fetus. • Family history Ultrasonographic ndings: Various ultra- • Ultrasonographic ndings sonographic ndings may be a manifestation • fleports of serum aneuploidy screen • of an underlying genetic syndrome in the fetus • Postmortem evaluation and a high degree of suspicion as well as careful • Genetic testing search for associated abnormality(ies) is important • Antenatal history: The woman should be to recognise these. asked• about history of potential teratogenic ex- a. Structural/ morphological abnormality: These posure in the form of prescription drugs, high most commonly are malformations i.e. intrinsic grade fever, exposure to environmental toxins and defects in the formation of a structure, but can infection with teratogenic pathogens like rubella, also be deformations due to compressive effects cytomegalovirus, etc. History of decreased fe- on a normally formed structure e.g. varus de- tal movement perception and malpresentations formity in oligohydramnios, or disruptions due to is important in cases with arthrogryposis, poly- sudden insult, traumatic or vascular on a normally hydramnios and small stomach bubble, where formed structure e.g. amputation due to amniotic these nds can provide a clue regarding a primary band. Malformations or intrinsic defects are likely neuromuscular disorder in the fetus. History of to be of genetic etiology. They may be isolated previous pregnancies is also important, as previous or may be associated with other malformations pregnancy losses, pregnancy terminations due to and/or growth problems which indicate an under- similar or overlapping ndings, neonatal deaths lying genetic syndrome. A specic spectrum of or previous live abnormal offspring all indicate abnormalities may be characteristic of a specic possible segregation of a genetic disorder in the genetic syndrome e.g. Meckel Gruber syndrome family. presents with encephalocele, polydactyly and mul- Medical history: History of maternal illness ticystic dysplastic kidneys; 13 presents with like• uncontrolled diabetes, phenylketonuria, thy- holoprosencephaly, midline cleft, polydactyly and roid disorders, etc. needs to be elicited as they can multicystic dysplastic kidneys; and similarly many play an important role in fetal growth and devel- other patterns of malformations indicating a par-

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Fetus with abnormality Historical details including pedigree

Antenatal Postmortem ultrasound examination

• Soft marker: Single or multiple; • Facial dysmorphism low risk or high risk • External or internal • Malformation: Isolated or malformation: Isolated or multiple multiple • Growth/liquor abnormality: • Growth abnormalities Isolated or associated with soft Organomegaly marker or malformation; • Skeletal dysplasia on radiographs Doppler studies or other • Histopathology of fetal organs indicators of acquired showing specific etiology etiologies • Placental histopathology showing • Adjunct modalities: fetal MRI, evidence of uteroplacental 3 D USG insufficiency

Invasive testing: Fetal tissue Amniocentesis/cordocentesis/ sampling placental biopsy

• Fetal karyotype • Chromosomal microarray • Biochemical testing • Exome sequencing

Diagnosis of fetal syndrome

Dashed arrow reflects that postmortem evaluation may or may not be done depending on ultrasound findings

Figure 2 Practical approach to fetal syndrome diagnosis. ticular diagnosis. As a rule, each has been statistically quantied. These risks per se indicate possibility of a genetic syndrome, are integrated with the maternal demographics and whereas a single malformation may or may not be serum screening risks to provide a nal aneuploidy genetic in etiology. risk, which is then used for decision-making regard- b. Soft markers: These are ultrasound ndings, ing invasive testing and fetal karyotyping. Similar which may be seen in many normal fetuses, but are to malformations, presence of multiple markers in- also indicators of underlying syndromic etiology, creases the risk of chromosomal aneuploidy more primarily chromosomal disorders in some fetuses. signicantly. Many soft markers have been described and the c. Growth abnormalities: Both fetal growth re- risk of chromosomal disorders associated with striction as well as fetal overgrowth can be due

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Fetal abnormality Genetic syndromes reported to be associated

Increased nuchal fold • Trisomy 21 thickness • Other • • Skeletal dysplasias: Achondrogenesis, osteogenesis imperfecta

Absent nasal bone • Trisomy 21 • Skeletal dysplasias: asphyxiating thoracic dystrophy, brachytelephalangic chondrodysplasia punctata Short long bones • Skeletal dysplasias: Various with distinctive features like fractures, bending, macrocephaly, polydactyly • Syndromes with primordial Multicystic dysplastic • Trisomy 13 • Meckel-Gruber syndrome and other ciliopathies

Figure 3 Common ultrasound abnormalities and associated genetic syndromes. to maternal and utero-placental factors or due derlying genetic etiology, such as low estriol levels to an intrinsic fetal abnormality. Besides chro- in SLOS and high alfa-fetoprotein in BWS. mosomal disorders, various single gene disorders d. Liquor abnormalities: Both excess and scanty like microcephalic osteodysplastic dwarsm, Seckel liquor can be due to underlying genetic etiologies, syndrome, Smith-Lemli Opitz syndrome (SLOS), eg Bartter syndrome in polyhydramnios and auto- flussel-Silver syndrome, etc. can present with somal recessive polycystic kidney disease in oligo- intrauterine growth restriction (IUGfl). Another im- hydramnios. At times, these could be indicators portant group of disorders presenting with short of other underlying morphological abnormalities, bones and mimicking IUGfl is the skeletal dyspla- indicating a syndromic diagnosis. sia group, which includes at least 100 different Figure 3 depicts some common ultrasound single gene conditions presenting in the prena- abnormalities and associated genetic syndromes. tal period. Fetal overgrowth may also be due Maternal serum screen: These are biomark- to primary overgrowth disorders like Beckwith- ers• in the maternal serum which are assayed Wiedemann syndrome(BWS), Pallister-Killian syn- with the primary aim to screen for common fetal drome and , among others. chromosomal abnormalities. Both rst and second Hence, it is important to look for additional nd- trimester screening protocols are available, which ings like facial dysmorphism and malformations in in combination with ultrasonic soft markers aid in all cases of fetal growth abnormalities, where no screening of low risk women for fetal chromosomal acquired etiology is apparent. At times, maternal disorders with high sensitivity and low false positive serum screen results can provide clues to the un- rates. However, these markers are primarily useful

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Postmortem external or internal abnormality Genetic syndromes reported to be associated

Radial ray defect • Trisomy 18 • VACTERL association • Fanconi anemia • TAR syndrome • SALL4 mutation • Rothmund-Thomson syndrome

Polydactyly • Trisomy 13 • Meckel-Gruber syndrome and other ciliopathies • Orofaciodigital syndrome • Pallister-Hall syndrome and other GLI3 disorders • At least 400 different disorders

Overlapping fingers • Trisomy 18 • Distal arthrogryposis • Otopalatodigital syndrome

Arthrogryposis multiplex • Trisomy 18 congenita • Multiple pterygium syndrome • Neuromuscular disorders • Skeletal dysplasias • Connective tissue disorders • At least 300 different disorders

Cleft Palate • 22q11.2 • Stickler syndrome • Smith-Lemli-Opitz syndrome • Otopalatodigital syndrome • Orofaciodigital syndrome Congenital diaphragmatic hernia • • Simpson-Golabi-Behmel syndrome • Pallister-Killian syndrome • Donnai -Barrow syndrome

Truncus arteriosus • 22q11.2 deletion • Trisomies • Holt –Oram syndrome • Townes-Brocks syndrome

Dandy-Walker malformation • Walker-Warburg syndrome • Trisomies • Ritscher-Schinzel syndrome • Meckel-Gruber syndrome • Congenital disorder of glycosylation • Orofaciodigital syndrome

Figure 4 Common postmortem dysmorphic ndings and associated genetic syndromes.

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Postmortem evaluation/fetal autopsy: This standard techniques. It is important to be aware involves• a comprehensive and step-wise evaluation of some normal gestation-dependent ndings, like of the fetus in a post-mortem setting and forms the the lobulated appearance of fetal kidney, the rel- single most important modality for diagnosis of a ative large size of adrenals, thymus and liver, the genetic syndrome. Typically, autopsy encompasses developing internal genitalia and ssures and an external examination or dysmorphological eval- the smooth brain surface in early gestation among uation of the fetus, similar to the approach in a others. Gestation-specic photographs should be clinical genetics clinic; internal dissection to look used for comparison before concluding a structure for gross morphological abnormalities of fetal or- as abnormal. Figure 5 provides some normal gans and structures; whole body radiogram, both gestation-dependent ndings. Figure 4 depicts antero-posterior and lateral views; and histopatho- some internal organ abnormalities and respective logical evaluation of fetal organs and placenta. A associated genetic syndromes. standard autopsy proforma helps in maintaining record of the ndings. Briey, the following are the steps, relevant ndings and implications during an autopsy: a. Radiographs: A complete fetal radiograph is essential for diagnosis of a skeletal dysplasia and in distinguishing the various types from each other. Cardinal features like platyspondyly, aring of ends of femur, bent femur, fractures, absent ossication, epiphyseal stippling, etc. all help in providing diagnosis of a specic condition. A radiograph can also provide ancillary information like joint dislocations, spine deformities, missing or supernumerary bones, etc., which may help in diagnosis of a specic genetic syndrome. b. External/Dysmorphological examination: This involves assessment of anthropometric parame- ters like crown rump length, crown heel length, head circumference, chest circumference and foot length. Other parameters like inter-orbital dis- tance, hand length, philtrum length, phallus length, Figure 5 Some gestation-dependent normal and limb segment length may also be assessed as morphological ndings in fetal life a: required. All the parameters should be compared Blake pouch cyst with normal cerebel- to available centile charts and recorded. This lum (inset) at 19 weeks; b: Smooth is followed by a head to toe examination with brain at 19 weeks gestation; c: Low special attention to dysmorphic features. The set and poorly formed ear placode in a head, , neck, spine, chest, abdomen, external rst trimester fetus; d: Lobulated fetal genitalia, extremities, joints and skin are assessed kidneys similar in size to fetal adrenals for shape, size and appearance, and any deviation at mid-trimester. from normal searched for and noted. The placenta, membranes and umbilical cord are also examined d. Gross examination and histopathology of fetal for appearance and any abnormality. The weight organs: All fetal organs are weighed and com- of the placenta and number of cord vessels are pared with gestation-dependent percentiles. A recorded. Figure 4 provides some dysmorphic detailed histopathological evaluation is performed, features and the corresponding genetic syndromes using H&E staining, and if necessary special stains associated with these. and immunohistochemistry. Many renal and c. Internal examination: This involves the exam- brain pathologies can be well delineated follow- ination of the intra-abdominal, intra-thoracic and ing histopathology and in many instances this intra-cranial structures for any abnormalities, in forms the sole basis for diagnosis. An example size, shape or morphology. Incision is made on the being cystic diseases of kidney, where histopathol- anterior aspect of the trunk and the skull following ogy can distinguish between autosomal recessive,

Genetic Clinics 2017 | April - June | Vol 10 | Issue 2 17 GeNeViSTA dominant polycystic kidneys, multicystic dysplastic orders is challenging in the laboratory as many kidneys and glomerulocystic kidney disease, all of conditions have overlapping features and genetic which can have a similar gross appearance and heterogeneity is common. Conventionally, most clinical presentation. Similarly, brain pathologies often the diagnosis was made following a post- like neuronal migration disorders can be well delin- mortem evaluation, and then subsequent targeted eated and classied on histopathology. Placental testing was done by Sanger sequencing of the histopathology can provide evidence of uteropla- causative gene in the fetal DNA. However, availabil- cental insufficiency and fetal infections. ity of the Next generation sequencing technology This comprehensive approach to an abnormal has made it easier to provide molecular testing, fetus, using historical, imaging and postmortem as this enables the parallel sequencing of mul- ndings provides important diagnostic information tiple enabling interrogation of overlapping and often leads to the diagnosis of a specic phenotypes as well as genetically heterogeneous dysmorphic syndrome or identication of an ac- conditions. An example would be the skeletal quired etiology. However, nal conrmation of a dysplasias, with at least 100 different single gene genetic etiology depends on laboratory testing and disorders presenting with short bones on antenatal identication of the underlying genetic aberration. ultrasound. Exact diagnosis is often not possible antenatally, and fetal sampling followed by a NGS- Genetic testing for the dysmorphic fetus based testing of all skeletal dysplasia genes can be done to arrive at a nal diagnosis and provide Genetic disorders can broadly be classied into accurate prognostication to the family. three different types, and each of these require a c. Genomic disorders: Another group of genetic specic laboratory diagnostic approach. diseases are caused by copy number abnormal- a. Chromosomal disorders: These are disorders ities in the genome i.e. small, submicroscopic arising due to numerical or structural abnormal- microdeletions or microduplications involving part ities in chromosomes. The common ones with of the genome. These conditions require special well described prenatal phenotypes are Down syn- molecular cytogenetic techniques for diagnosis, drome (Trisomy 21), (Trisomy 13), and often in the antenatal period, where a spe- Edward syndrome (Trisomy 18), cic diagnosis is not apparent, a chromosomal and triploidy. A karyotype from the amniotic uid microarray is the most common testing modality (following amniocentesis), cord blood (following used. Various antenatal series have found that cordocentesis or at birth), intra-cardiac blood (post chromosomal microarray studies from fetal DNA mortem) or skin broblasts, is the gold standard of a morphologically abnormal fetus indicate a for the diagnosis of this group of disorders. These copy number abnormality in 6-10% (de Wit et al., on average constitute 10-30% of fetuses with an 2014). Presently, microarray studies are recom- antenatal malformation (Beke et al., 2005). Since mended as rst tier test in case of morphological karyotyping requires the presence of viable cells, it abnormalities on ultrasound. Postnatal studies is essential to obtain suitable samples antenatally have also found 2-10% of stillbirths as having copy or soon after birth for this investigation. number abnormalities, indicating the signicant b. Single gene disorders/ Mendelian disorders: contribution of this group of genetic aberrations to These are diseases arising due to in in- fetal abnormalities (fleddy et al.,2012). dividual genes. At least 6000 single gene disorders d. A relatively rarer type of genetic disorders have been described and for 4500 of them the known as imprinting disorders can also present molecular basis is known. Many of these disorders with fetal abnormalities, primarily affecting growth. present in the prenatal period with fetal abnormali- Examples being Beckwith-Wiedemann syndrome ties, some common examples being Meckel-Gruber presenting with overgrowth, organomegaly, om- syndrome, Noonan syndrome, short rib polydactyly phalocele and polyhydramnios; and flussel-Silver syndromes, lysosomal storage disorders, etc. The syndrome presenting with fetal growth restriction. exact estimate of such disorders in the prenatal Testing for these conditions requires methylation period is not known, however some recent stud- studies on fetal DNA. ies employing Next generation sequencing-based Unlike samples for karyotyping, which require novel technologies have found single gene defects viable cells, fetal DNA can be obtained from any in 20-30% of fetuses with antenatal malformations fetal sample, including an umbilical cord seg- (Drury et al., 2015). The diagnosis of these dis- ment, either antenatally or post-mortem. The

Genetic Clinics 2017 | April - June | Vol 10 | Issue 2 18 GeNeViSTA only prerequisite for suitable DNA sample is that tion in the affected fetus. Hence, laboratory genetic the concerned sample should not be exposed to testing and conrmation of the clinical diagnosis formalin, which can lead to cross linkage, adduct plays an important role in fetal dysmorphology. formation and fragmentation of DNA, precluding Once the exact mutation or chromosomal abnor- further molecular studies. Hence, to facilitate mality or biochemical defect in the index case laboratory testing and conrmation of a genetic is known, early and denitive prenatal diagnosis diagnosis, suitable fetal sample should be obtained is possible by chorionic villus sampling at 11-12 and stored if immediate testing is not possible. weeks in subsequent conceptions. In absence of Storage for purpose of DNA extraction can be done a laboratory diagnosis, prenatal diagnosis can be at 2-8⁰C for few weeks and at -20⁰C for long term. attempted by ultrasound, however this may not For karyotyping, sample can be stored at 2-8⁰C be of utility till later in pregnancy, and milder or and be transferred to the laboratory as soon as discordant manifestations may not be detected. possible, and at least within 48 hours. These issues need to be discussed with the family prior to pregnancy termination, so that appropriate Genetic counseling fetal samples can be obtained. Appropriate genetic counselling is possible after Conclusion an accurate diagnosis has been made following the clinical and laboratory evaluations. Counseling Feta dysmorphology plays an important role in typically addresses the following issues: evaluation of an abnormal fetus with far reach- 1. Prognosis: This is relevant in the antenatal ing implications for the current as well as future setting when a couple is faced with an ultrasound pregnancies. A multi-disciplinary approach, with diagnosis of a fetal abnormality. Besides the clinical geneticist playing a pivotal role is integral to morbidities of the abnormality and outcome of optimising the care of these special patients and postnatal surgery in structural abnormalities, the their families. recognition of a syndrome has various implica- tions. Most genetic syndromes are associated with References intellectual handicap, which does not have a satis- factory therapy. Additionally, there can be growth 1. Beke A, et al. Trisomies and other chromo- issues, presence of other internal malformations some abnormalities detected after positive not detectable by imaging, and occasionally pre- sonographic ndings. J fleprod Med 2005; 50: mature lethality. This information needs to be 675-691. communicated to the couple as it helps in decision 2. de Wit MC, et al. Additional value of prenatal making regarding pregnancy termination, obstetric genomic array testing in fetuses with isolated management as well as neonatal management. structural ultrasound abnormalities and a nor- 2. Recurrence risk: There is an increased recur- mal karyotype: a systematic review of the rence risk associated with genetic etiologies, which literature. Ultrasound Obstet Gynecol 2014; is 25% for autosomal recessive disorders, 50% for 43:139-146. an autosomal dominant disorder with affected par- 3. Drury S, et al. Exome sequencing for prenatal ent and 50% for male offspring of a carrier female diagnosis of fetuses with sonographic abnor- for X-linked recessive disorders. The risk is low malities. Prenat Diagn 2015; 35:1010-1017. for chromosomal disorders, unless they arise due 4. fleddy UM, et al. Karyotype versus microarray to a parental chromosomal rearrangement and testing for genetic abnormalities after stillbirth. for autosomal dominant disorders with normal N Engl J Med 2012; 367: 2185-2193. parents. This risk estimate helps the couple in 5. flodriguez MA, et al. Concordance between availing prenatal diagnosis services in subsequent prenatal ultrasound and autopsy ndings in a pregnancies, and the need and availability of the tertiary center. Prenat Diagn 2014; 34: 784-789. same should be communicated. 6. Stoll C, et al. Prenatal diagnosis of dysmorphic 3. Prenatal diagnosis: The pre-requisite to deni- syndromes by routine fetal ultrasound examina- tive prenatal diagnosis in subsequent pregnancies tion across Europe. Ultrasound Obstet Gynecol is identication of the underlying genetic aberra- 2003; 21: 543-551.

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