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The explicit naming of a specific genetic disorder when the family history is being discussed facilitates evaluation and any possible testing. Difficulties are introduced when neither family nor previous physicians have recognized a genetic disorder within the family, sometimes revealed by expanded carrier screening⁵⁹¹ or whole‐exome sequencing.⁵⁹² Such a disorder may be common (e.g. factor V Leiden deficiency) but nevertheless unrecognized. Clinical clues would include individuals in the family with deep‐vein thrombosis, sudden death possibly due to a pulmonary embolus, and yet other individuals with recurrent pregnancy loss.⁵⁹³ Venous thromboembolism is the third leading cause of cardiovascular death in the United States, and provides additional insights into the genetic basis of unprovoked pulmonary embolism. Using whole‐exome sequencing in 393 affected individuals and 6,114 controls, Desch et al.⁵⁹⁴ identified four genes (PROS1, STAB2, PROC, SERPINC1) with pathogenic variants, expanding the need for genetic testing given the history of thromboembolism.

For some families, individuals with quite different apparent clinical features may, in fact, have the same disorder. Seventeen cancers in different organs in family members may not be recognized as manifestations of the same common mutation. In hereditary nonpolyposis colon/rectal cancer, various family members may suffer from other cancers including the uterus, ovary, breast, stomach, small bowel, ureter, melanoma, or salivary glands. Analysis of the five culprit genes in the proband would enable detection of the mutation, which could then be assayed in other family members at risk. In another example, there may be two or more deceased family members who died from “kidney failure,” and another one or two who died from a cerebral aneurysm or a sudden brain hemorrhage. Adult polycystic kidney disease (APKD) may be the diagnosis, which will require further investigation by both ultrasound and DNA analysis. Moreover, two different genes for APKD have been identified (about 85 percent of cases due to APKD1 and close to 15 percent due to APKD2),⁵⁹⁵ and a rare third locus is known. In yet other families, a history of hearing impairment/deafness in some members and sudden death in others may translate to the autosomal recessive Jervell and Lange–Nielsen syndrome.⁵⁹⁶ This disorder is characterized by severe congenital deafness, a long QT interval, and large T waves, together with a tendency for syncope and sudden death due to ventricular fibrillation. Given that a number of genetic cardiac conduction defects have been recognized, a history of an unexplained sudden death in a family should lead to a routine electrocardiogram at the first preconception visit and possibly mutation analysis of at least 15 long QT syndrome genes.⁵⁹⁷ Other disorders in which sudden death due to a conduction defect might have occurred, with or without a family history of cataract or muscle weakness, should raise the suspicion of myotonic muscular dystrophy (see Chapter 31).

Rare named disorders in a pedigree should automatically raise the question of the need for genetic counseling. We have seen instances (e.g. pancreatitis) in which, in view of its frequency, the disorder was simply ascribed to alcohol or idiopathic categories. Hereditary pancreatitis, although rare, is an autosomal dominant disorder for which several genes are known.⁵⁹⁸

Awareness of the clinical manifestations in carrier females of X‐linked disorders is important given health and risk implications (Table 1.7). The pattern of inheritance of an unnamed disorder may signal a specific monogenic form of disease. For example, unexplained intellectual disability on either side of the female partner's family calls for fragile X DNA carrier testing. Moreover, unexpected segregation of a maternal premutation may have unpredicted consequences, including reversion of the triplet repeat number to the normal range.⁶⁷¹ Genetic counseling may be valuable, more especially because the phenomena of pleiotropism (several different effects from a single gene) and heterogeneity (a specific effect from several genes) may confound interpretation in any of these families.

Table 1.7 Signs in females who are carriers of selected X‐linked recessive disease pertinent to prenatal diagnosis.

Selected disorders	Key feature(s) that may occur	Selected references
Aarskog–Scott syndrome allelic with XLMR 16	Widow's peak or short stature	599
Achromatopsia	Decreased visual acuity and myopia	600
Adrenoleukodystrophy	Neurologic and adrenal dysfunction	601 , 602
Alport syndrome	Microscopic hematuria and hearing impairment	603
Ameliogenesis imperfecta, hypomaturation type	Mottled enamel vertically arranged	604
Arthrogryposis multiplex congenita	Club foot, contractures, hyperkyphosis	605
ATRX syndrome α‐thalessemia/ID syndrome	Mild intellectual disability, hemoglobin H inclusions	599 , 606
Borjeson–Forssman–Lehmann syndrome	Tapered fingers, short, widely spaced, flexed toes, mild mental retardation	607
Choroideremia a	Chorioretinal dystrophy	608
Chondrodysplasia punctata 1	Mild intellectual disability, possible bone defects and short stature	599
Chronic granulomatous disease	Cutaneous and mucocutaneous lesions	609 – 611
Cleft palate	Bifid uvula	612
Conductive deafness with stapes fixation	Mild hearing loss	613
Deafness X‐linked 1 allelic with Charcot‐Marie‐Tooth 5	Mild high‐pitch hearing loss	599
Dilated cardiomyopathy	Cardiac failure	614
Duchenne/Becker muscular dystrophy	Pseudohypertrophy, muscle weakness, cardiomyopathy/conduction defects	615 – 618
Dyskeratosis congenita	Retinal pigmentation	619
Ectodermal dysplasia	Variable severity of skin, hair, nails, and teeth	599
Emery–Dreifuss muscular dystrophy	Cardiomyopathy/conduction defects	620 – 622
Fabry disease	Angiokeratomas, corneal dystrophy, "burning" hands and feet, rhabdomyolysis	623 , 624
FG syndrome	Anterior displaced anus, facial dysmorphism	625
Fragile X syndrome	Mild‐to‐moderate intellectual disability, behavioral aberrations, schizoaffective disorder, premature ovarian failure, fragile X tremor ataxia syndrome, women and men premutation carriers	626–628 (see Chapter 16)
G6PD deficiency	Hemolytic crises, neonatal hyperbilirubinemia	629
Hemophilia A and B	Bleeding tendency	630
Hypohydrotic ectodermal dysplasia	Sparse hair, decreased sweating	631 , 632
Ichthyosis	Ichthyosis	633
KDM5C gene disease	Intellectual disability	634
Lissencephaly and agenesis of the corpus callosum	Epilepsy with subcortical band heterotopia	599
Lowe syndrome	Lenticular cataracts	635
MASA syndrome/SPG1	Mild intellectual disability, abducted thumbs	599
McLeod neuroacanthocytosis syndrome	Chorea, late‐onset cognitive decline	636
Menkes disease	Patchy kinky hair, hypopigmentation	637 , 638
Myopia	Mild myopia	639
Nance–Horan syndrome b	Posterior Y‐sutural cataracts and dental anomalies	640
Norrie disease	Retinal malformations	641
Ocular albinism type 1	Retinal/fundal pigmentary changes	642
Oculofaciodigital syndrome (OFD1) allelic with Simson–Galabia–Beheld syndrome 2 and Joubert syndrome	Facial dysmorphism, abnormal digits, and polycystic kidneys	599
Oligodontia	Hypodontia	643
Opitz G/BBB syndrome	Hypertelorism	644
Opitz–Kaveggia syndrome	Mild intellectual disability, hypertelorism	599
Ornithine transcarbamylase deficiency	Hyperammonemia, psychiatric/neurologic manifestations	645 , 646
Ovarian cancer	Ovarian cancer	647
Pelizaeus–Merzbacher	Possible mild spasticity	648
Retinoschisis	Peripheral retinal changes	649
Retinitis pigmentosa	Night blindness, concentric reduction of visual field, pigmentary fundal degeneration, extinction of electroretinogram, cone disruption, vision loss	650 , 651
MECP2‐duplication syndrome	Intellectual disability, neuropsychiatric features, endocrine abnormalities	652
Simpson–Golabi–Behmel syndrome	Extra lumbar/thoracic vertebrae, accessory nipples, facial dysmorphism	653 , 654
Spinal and bulbar muscular atrophy	Muscle weakness and cramps	655
Split‐hand/split‐foot anomaly	Mild split‐hand/split‐foot anomaly	656
Spondyloepiphyseal dysplasia, late onset	Arthritis	657
Ulnar hypoplasia with lobster‐claw deficiency of feet	Slight hypoplasia of ulnar side of hand and mild syndactyly of toes	658
Wiskott–Aldrich syndrome a	Abnormal platelets and lymphocytes	659 , 660
X‐linked intellectual disability	Mostly intellectual disability (many genes), occasional short stature, hypertension, psychiatric symptoms	661 – 663
X‐linked mental retardation	Short stature, hypertelorism	599 , 664 , 665
X‐linked mental retardation (OPHN1)	Cerebellar hypoplasia, distinctive facies	666 , 667
X‐linked myotubular myopathy	Weakness, respiratory problems	668
X‐linked protoporphyria	Life‐long photosensitivity; liver disease	669
X‐linked retinitis pigmentosa	Retinal changes	670

^a Uncertain.

^b May be same disorder.

History of a previous child with intellectual disability with a diagnosis deemed “idiopathic” or of unknown cause after chromosomal, fragile X and biochemical analyses, is no longer tenable without whole‐exome sequencing^{672, 673} (see Chapter 14). Over 700 genes involved in intellectual disability of monogenic origin have been recognized.^{674, 675} In a meta‐analysis of 3,350 individuals with neurodevelopmental disorders^676–678 the diagnostic yield was 36 percent using whole‐exome sequencing. More recently, whole‐exome sequencing for patients sent for a chromosomal microarray yielded diagnoses in about 27 percent of intellectual disability cases.⁶⁷⁶