Somatic mosaicism has been described in almost all autosomal dominant disorders. Tissue‐ or organ‐specific segmental mosaicism explains certain overgrowth syndromes exemplified by the PIK3CA‐associated developmental disorders that result in focal overgrowth, brain overgrowth, or capillary malformations with overgrowth.868–870
A remarkable example of focal growth due to somatic mosaicism was the hyperinsulinism noted in an infant without any signs of the Beckwith–Wiedemann syndrome. Following removal of 80 percent of the pancreas, atypical histological features with enlarged hyperchromatic nuclei in islets were observed. Methylation analysis, a chromosomal microarray, and short tandem repeat markers led to a diagnosis of mosaic segmental paternal uniparental disomy 11p15.5‐p15.1 in pancreatic tissue, but not in the infant's blood.871
Brain somatic mutations occurring during cortical development may result in sporadic intractable epilepsy.872 One study focused on the parents of children with Dravet syndrome due to SCN1A mutations.873 SCN1A mosaicism was found in 5.2 percent (30 out of 575) of families with affected children. Discovery of an oncogene (e.g. RB1) for retinoblastoma occurring in the absence of a family history, will inevitably lead to examination of the parents to determine recurrence risk. An analysis using targeted deep sequencing of the parents of 124 offspring with bilateral retinoblastoma revealed only one parent with somatic mosaicism for the deleterious RB1 mutation, a 0.4 percent risk of recurrence.874
Over 700 genes are linked to neurodevelopmental disorders, some with epilepsy. Discovery of a putative de novo mutation now invariably leads to genomic evaluation of both parents in a search for somatic mosaicism. Disorders in this category include intellectual disability, epileptic encephalopathies, cerebral cortical malformations, and autism spectrum disorders.875, 876
In a study of 10,362 consecutive patients, over 1 in 200 were shown to have somatic mosaicism.877 In that study, mosaicism was detected for aneuploidy, ring or marker chromosomes, microdeletion/duplication copy number variations, exonic copy number variations, and unbalanced translocations. Examples include hypomelanosis of Ito, other syndromes with patchy pigmentary abnormalities of skin associated with intellectual disability, and some patients with asymmetric growth restriction.878, 879 Gonadal mosaicism (see Chapter 14) should be distinguished from somatic cell mosaicism in which there is also gonadal involvement. In such cases, the patient with somatic cell mosaicism is likely to have some signs, although possibly subtle, of the disorder in question, while those with gonadal mosaicism are not expected to show any signs of the disorder. Current methodologies for clinical and prenatal diagnosis invariably list detection of very low degrees of mosaicism in a caveat that accompanies the reports. Additional examples of somatic and gonadal mosaicism include autosomal dominant osteogenesis imperfecta,880, 881 Huntington disease,882 and spinocerebellar ataxia type 2.883 Lessons from these and the other examples quoted for gonadal mosaicism indicate a special need for caution in genetic counseling for disorders that appear to be sporadic (see Chapter 14).
Very careful examination of both parents for subtle indicators of the disorder in question is necessary, particularly in autosomal dominant and sex‐linked recessive conditions. The autosomal dominant disorders are associated with 50 percent risks of recurrence, while the sex‐linked disorders have 50 percent risk for males and 25 percent risk for recurrence in families. Pure gonadal mosaicism would likely yield risks considerably lower than these figures, such as 4–8 percent for females with gonadal mosaicism and X‐linked DMD. A second caution relating to counseling such patients with an apparent sporadic disorder is the offer of prenatal diagnosis (possibly limited) despite the inability to demonstrate the affected status of the parent.
Chromosomal mosaicism is discussed in Chapter 11 but note can be taken here of a possibly rare (and mostly undetected) autosomal trisomy. A history of subfertility with mostly mild dysmorphic features and normal intelligence has been reported in at least ten women with mosaic trisomy 18.884
Genetic counseling when the fetus is affected
The fateful day when the anxious, waiting couple hears the grim news that their fetus has a malformation or genetic disorder will live on in their memories forever. Cognizance of this impact should inform the thoughts, actions, and communications of the physician or counselor called on to exercise consummate skill at such a poignant time. Couples may have traveled the road of hope and faith for many years, battling infertility only to be confronted by the devastating reality of a fetal anomaly. With hopes and dreams so suddenly dashed, distress, doubt, anger, and denial surface rapidly. The compassionate physician or counselor will need to be fully armed with all the facts about the defect or be ready to obtain an immediate expert clinical genetics consultation for the couple.
Care should be taken in selecting a quiet, comfortable, private location that is safe from interruption. The language used should be clear and without jargon. Attention to a patient's cultural background and possible need for an interpreter is important. This is a communication not to be rushed but characterized by sensitivity and empathy. Informing a couple with bad news about the fetus by telephone or email is unacceptable. Arrangements for a follow‐up visit and support where needed is advisable. Ptacek and Eberhardt969 and others,970 in reviewing the literature, noted consensus recommendations in breaking bad news that included the aforegoing and sitting close enough for eye contact without physical barriers. Identifying a support person, if the partner cannot/will not attend the consultation, is important and knowledge of available resources is valuable. All of the above points are preferences that have been vocalized by parents receiving bad news during pregnancy or about their infants.971
Almost all couples would have reached this juncture through maternal serum screening, noninvasive prenatal testing, an ultrasound or MRI study, or amniocentesis/CVS for maternal age, for established known carriers, because of a previously affected child, being an affected parent, or having a family history of a specified disorder. More recently, prenatal diagnosis using whole‐exome sequencing972 has led to the diagnosis of unexpected genetic disorders, and in the process introduced ethical issues and challenging quandaries.973, 974 Commonly, an anxious patient insists on a prenatal study. Physicians are advised not to dissuade patients from prenatal diagnosis but rather to inform them about the risks of fetal loss balanced against the risk of fetal abnormality, distinctly different from recommendations for accepted indications. Given the low risks, prenatal diagnosis can be offered to all couples (see Chapter 9).
Recognition of a fetal abnormality by imaging, molecular, or cytogenetic study may reveal, for the first time, the genetic disorder in an affected asymptomatic parent. Robyr et al.975 described 20 such parents with disorders including spinal muscular atrophy, DiGeorge syndrome, osteogenesis imperfecta, arthrogryposis, and Noonan‐like syndrome.
Frequently, second‐trimester ultrasound studies reveal fetal abnormalities of uncertain etiology with a subsequent normal karyotype. A chromosomal microarray may enable a precise diagnosis in 6–8.1 percent976, 977 (see Chapter 13). In a legal case, sequential observations noted prominent lateral cerebral ventricles, multiple thoracic hemivertebrae, and intrauterine growth restriction. Amniocyte chromosome studies were normal. The parents were not counseled about the potential for intellectual disability despite no definitive diagnosis. The child was born with holoprosencephaly with marked psychomotor delay. Diagnostic uncertainty must be shared with parents at risk. Uncertainty
