🧬 PART SEVEN PHENOTYPES

25 PARTICULAR PHENOTYPES Most chapters in this book start with the chromosome: an abnormality has been found, and we—the patient and counselor both—need to know more. Obviously enough, the discovery of a chromosomal abnormality then leads to a discussion about the phenotypic consequences, either as already seen in the person concerned, or in their family, or as a future possibility; and elsewhere in this book considerable detail attests apropos. In this chapter we take the opposite view and start with the phenotype: what particular phenotypes might be due to what particular chromosomal abnormality and which might therefore lead to a consideration for a chromosome analysis. We limit ourselves to a discussion of only a few conditions—the full range would require a new book!—namely, those in which a link to certain chromosomal scenarios has been well established and for which we consider some commentary might be useful. The reader may appreciate, in outline, the very broad extent of chromosomally caused disease with reference to the “malformation map” in Figure 3–20. ALZHEIMER DISEASE Familial autosomal dominant Alzheimer disease is due mostly to point mutation within PSEN1, with a minority due to mutation in APP (amyloid precursor protein) or PSEN2. A tiny fraction reflect a duplication of the APP locus. This may be as a CNV duplication (Figure 25–1) or as an insertion into another chromosome (Figures 14–79 and 14–80). The near-inevitable evolution of Alzheimer’s in Down syndrome individuals as they enter middle age reflects this same APP dosage effect (Figure 13–2). ATAXIA AND MOVEMENT DISORDERS Much the most useful tool in identifying the genetic basis of an ataxia syndrome is mutation testing, either targeted according to the clinical picture presented or by way of a multiplex approach using a broad-band ataxia gene panel. But occasionally a microdeletion or a CNV might cause an intragenic deletion that could be missed on classical DNA methodology. An example is seen in spinocerebellar ataxia type 15 (SCA15) in which an intragenic deletion within ITPR1 is a recognized cause of the disorder. Ghorbani et al. (2023) screened 338 cases of undiagnosed ataxia on SNP array and could establish a firm diagnosis in only two (who actually turned out to be related) with deletion-based SCA15. We mention on p. 422 the case of a woman diagnosed with autosomal recessive spastic ataxia of Charlevoix and Saguenay (ARSACS) due to a CNV on one chromosome removing the locus concerned and exposing a mutation on the other chromosome; or in other words, reducing a pathogenic variant on the other chromosome to hemizygosity.

774  PHENOTYPES Parkinson disease, the classic movement disorder of adulthood, is somewhat more frequently seen in those with a sex chromosome aneuploidy and in those with the del 22q11.2, the latter chromosomal diagnosis not necessarily having been made before the onset of Parkinsonism (Carvalho et al. 2021). Movement disorders of childhood include ataxia, stereotypies, dystonia, chorea, tremor, myoclonus, paroxysmal dyskinesia, and spastic paraparesis. In the review of Soliani et al. (2023), the majority of such cases were seen in association with developmental delay/intellectual disability. Of the few with normal intellect, CNVs including these loci were ascertained: NKX21, KMT2B, and HNRNPU (which lies within 1q44, p. 381), SGCE (which lies within 7q21.3, p. 406), PRRT2 (a locus within the proximal BP4-BP5 deletion 16p11.2, p. 433), and NIPA1 (which is included within the Prader-Willi/Angelman segment, p. 426). AUTISM Autism is a frequent reason for a chromosome test to be requested (Ceylan et al. 2018; Jang et al. 2019). The term encompasses a wide range of symptomatology, acknowledged in the term “autism spectrum disorder.” At one end of the spectrum there is Asperger syndrome, which may be seen with higher IQs and certain extraordinary intellectual abilities but with persistent difficulties with social interaction and communication; at the Figure 25–1.  Duplications Encompassing APP. Notes: These dup CNVs were identified in a series of cases of early-onset Alzheimer’s disease. The asterisk shows the relative position of APP. Some have APP as the only contained gene, others are more extensive and include other loci. All but one were familial. The ages of onset were from 42 to 63 years, with ages at death from 42 to 68. Source: From L Grangeon et al., Phenotype and imaging features associated with APP duplications, Alzheimers Res Ther 15:93, 2023. Courtesy L Grangeon, and with the permission of Springer Nature. Chromosomal Phenotypes  775 other, profound intellectual disability. More typically the autistic phenotype describes a person whose language development and educational ability may not be far below average but who cannot interact normally at a social level, who struggles with social reciprocity, and who lacks the psychological flexibility to accommodate to an unfamiliar environment. The formal definition also includes a communication deficit, restricted/ repetitive behavior, and hyper- or hypo-reactivity to sensory input. A pre-eminent causative role of genetics is beyond argument (Khogeer et al. 2022). It is certainly common worldwide (Salari et al. 2022). If the term autism spectrum disorder may be seen as a somewhat “lumping” approach, chromosome testing might offer a “splitting” insight. That is to say, a chromosome abnormality, a del or a dup, is seen more particularly in children with more complex phenotypes where there is more likely to be intellectual disability, delay in motor milestones, and in whom there may also be a concomitant minor dysmorphology or growth disorder. This might be spoken of as “autism plus” (or “chromosomal autism”) or on the other hand, perhaps from a standpoint of intellectual handicap with behavioral disorder, as the foregoing “plus autism.” Another expression for this is “syndromic autism,” which stands in contrast to “pure/idiopathic autism” (or “polygenic autism”). Subtle differences are seen in the autism of chromosomal syndromes versus pure autism (Bozhilova et al. 2023). Certain chromosomal segments are particularly represented among the genomic imbalances observed in autism (Calle Sánchez et al. 2022; Raznahan et al. 2022; Fu et al. 2022; Wright et al. 2024), and Figures 25–2 and 25–3 draw attention accordingly. Chromosomes 15, 16, and 22 are obvious standouts, often occurring in the setting of a syndromic picture. In addition to the more commonly seen del/dups (Table 25–1), several other del/dups were recorded more than once in the large series of Wright and colleagues and include the following, seen in four or more cases: del 1q44, dup 2p25.3, del 2q37.3, del 5q34, del 6p21.33, dup 9q34.11, and dup 22q11.23. The 8p21.3 deletion is implicated in Cosemans et al. (2021). At the level of brain morphology, Modenato et al. (2021) analyzed brain MRI scans from patients with eight “neuropsychiatric” CNVs, documenting anatomical differences and thus confirming a direct physical effect due to the genomic imbalances (Figure 25–4). There is some genetic overlap with other neuropsychiatric conditions, including major depressive disorder, attention deficit hyperactivity disorder, and schizophrenia (Figure 18–6). The male excess in autism has long been known. One contributor to this excess may be deletion at Xp22.11, a segment that includes the DDX53 gene (Figure 25–5). These several chromosomal culprit regions notwithstanding, the clinical return from a standard chromosome study is modest but important. In a study of 201 mostly (80%) self-referred cases in New Zealand (which excluded those with a previously identified causal CNV), 6% had a presumed or likely contributory del, dup, or translocation (Figure 25–6). From Iran, of 36 cases from 30 families, Ghasemi et al. (2022) found only two examples of a presumed contributory chromosome deletion or del/dup rearrangement. These fractions of about 5%–10%,1 are typical. It remains the case that most 1 This range is above the figure seen (3%) in the large study of Wright et al.; these latter authors suggest that their figure may be a more accurate reflection overall, due to a less stringent threshold of acceptance of the diagnosis.

776  PHENOTYPES autism will be categorized as polygenic (with many risk alleles identified; Mahjani et al. 2021; Wright et al. 2024) or idiopathic. Genetic Counseling Genetic testing in autism can be a fraught matter. What benefits might parents expect to see, and what reactions might they actually have (Lucas et al. 2022)? Having identified a putative autism-associated del/dup in a proband, a challenge for the counselor lies in conveying the interpretation. A particular sensitivity will apply if an invitation to proceed to parental sampling is accepted. If a del/dup has arisen de novo, a risk of recurrence (barring a gonadal mosaicism) is low indeed—assuming, that is, that the del/dup was truly causative (and a de novo CNV has a greater likelihood of having been causative than a familial CNV). This category will be seen not infrequently. But if a parent proves to carry the same del/dup, there is a quandary to be faced. Might an astute and observant counselor see in that parent “microsigns” of autism? If so, how might such a delicate question be raised, if at all? And if there is a question of having further children, what sort of risk advice might be offered? The matters of nonpenetrance and variable expressivity, and the role of the familial background genome otherwise (Cirnigliaro et al. 2023), may become notions of considerable practical relevance. The risk to transmit a del/dup will be a simple Mendelian 50%. But the question, then, of the modifying effect of the contribution of the other parent—why did the index child Figure 25–2.  The Deletions and Duplications Most Commonly Associated with Autism. Notes: Red = deletion, blue = duplication, for the 13 most commonly observed segments. The percentages shown here represent the fractions of all autism-associated del/dups. These data came from the study of 21,532 individuals, in a US-wide survey of autism: participants were recruited online and in-person at clinical sites across the country. The majority (83%) were minors at the time of enrolment, 8% were independent adults, and 9% were dependent adults enrolled by a parent. The ratio of males to females with autism was (as is quite typical) 3.3:1. Those with a CNV (as shown here) comprised only 3% of the whole cohort. The remarkable involvement of chromosomes 15, 16, and 22 is to be noted. Source: Drawn from data in JR Wright et al., Return of genetic research results in 21,532 individuals with autism, Genet Med 26:101202, 2024. Chromosomal Phenotypes  777 have autism, but not the del/dup parent?—is certainly not simple. For the more commonly seen imbalances, the data displayed in Figure 25–3 and set out in Table C in the Appendix may give a sense of how potent is the functional impact (which is to say, the penetrance) in each, in terms of leading to an autism phenotype. The question may then arise of targeted testing in a future pregnancy. • Preimplantation Testing. In the case of “pure” autism, the fact of a male predominance has led some to seek sex selection at PGT in order to choose a female embryo for a subsequent pregnancy2 (Amor and Cameron 2008). With specific reference to “chromosomal autism” (in other words, CNV-associated) and in which a cognitive component is more likely to be a part of the phenotype, the clearest answer may come from PGT. Leahy et al. (2024) prove the point that PGT is feasible, and describe a 41-year-old mother from whom three of five embryos were dup15q11-13, and she herself then shown to be a carrier (but all five embryos being otherwise aneuploid). In principle, an embryo carrying this autism-associated duplication could be excluded from transfer; but in the awareness that the existence of autism is not necessarily predictable, were the Figure 25–3.  Frequencies of Certain Autism-Associated Deletions and Duplications. Notes: The population frequencies are shown of certain cytogenetic abnormalities, and the likelihoods of their being associated with autism. Deletions are red circles, duplications blue squares. The imbalances range from a near-harmless effect due to the 15q11.2del, with an odds ratio barely over 1, and not uncommon in the general population (about 1 person in 300); and towards the other end of the scale, the “Williams duplication”, 7q11.23dup, having a high risk to lead to autism (odds ratio about 30-fold), but also being a rare observation (near 1 in 100,000). In other words, the 15q11.2del is close to being non-penetrant, whereas the 7q11.23dup is fully penetrant. Source: Redrawn as a composite figure from data of A Raznahan et al., Convergence and divergence of rare genetic disorders on brain phenotypes: A review, JAMA Psychiatry, 79:818-828, 2022; and JM Fu et al., Rare coding variation provides insight into the genetic architecture and phenotypic context of autism, Nature Genet 54, 1320–1331, 2022. Most estimates were very close between the two studies; where a difference was notable, an intermediate point was chosen. 2 In the extensive study of Fu et al. (2022) comprising a little over 20,000 autism cases, it is seen that this sex difference includes the particular category of CNV-associated autism.

778  PHENOTYPES pregnancy to have proceeded.3 These issues, and implications more broadly of undertaking genetic testing in autism, are debated at length in Klitzman et al. (2024). • Prenatal Diagnosis has the capacity to detect small imbalances. Libman et al. (2024) surveyed mothers’ hypothetical views and found that the question of penetrance was a key factor in deciding whether or not the discovery of a “susceptibility locus” at prenatal diagnosis should be made known. Van der Steen et al. (2016) assess actual parental reactions to having been advised, following invasive prenatal diagnosis, that a susceptibility locus has been identified. They debate the pros and cons of revealing such a discovery and emphasize the need for an immediate access to tailored counseling. With respect to the most common autism-associated CNVs, at 16p11.2, Yue et al. (2024) surveyed a little over 20,000 women presenting for amniocentesis for a variety of reasons and identified 15 deletions and five duplications at 16p11.2. In the considerable majority parental phenotypes were normal, and in about half, the del/dup was carried by a parent. Most chose termination in the case of a deletion (whether BP 2-3 or BP 4-5), while in the small number of duplications the pregnancies proceeded to live birth. Table 25–1.  The Key Coordinates of the Most Commonly Seen Deletion and Duplication Segments in Autism SEGMENT del dup COORDINATES TYPICALLY SPANNED 1q21.1-q21.2 8 22 146.2 Mb–149.1 Mb 2p16.3 16 – 50.9-51.0 Mb 3q29 9 5 196.0 Mb–197.5 Mb 7q11.23 9 16 73.3 Mb–74.8 Mb 15q11.2 – 42 23.4 Mb–28.3 Mb 15q13.3 – 33 30.3 Mb–32.1 Mb 16p11.2 63 49 28.7 Mb–30.2 Mb 16p13.11 11 – 15.03 Mb-16.39 Mb 17p13.3 – 11 1.28 Mb–1.72 Mb 17q12 15 18 3.62 Mb–3.77 Mb 21q11.2-q22.3 – 20 2.56-Mb–.66 Mb 22q11.21 20 28 1.85 Mb–2.10 Mb 22q13.33 24 3 4.84 Mb–5.07 Mb Notes: The numbers in the del and dup columns indicate how many cases of each imbalance were identified among a whole cohort of 21,532 cases. The molecular coordinates (based upon hg38) identify the region within which the presumed key pathogenic segment lies. Some will have del/dups extending beyond these coordinates; other del/dups will be smaller, but nevertheless lying within the regions noted. In other words, in each case listed above, there is a common region of overlap (CRO); presumably the autism-susceptible factor in each is contained within this CRO and in some, an actual candidate is known or proposed. Source: From JR Wright et al., Return of genetic research results in 21,532 individuals with autism, Genet Med 26:101202, 2024. 3 If a role for epigenetic imprinting becomes better understood, medication during pregnancy to influence fetal methylation may come to have a place; but this is, as yet, speculative (LaSalle 2023; Ravaei et al. 2023). Chromosomal Phenotypes  779 Figure 25–4.  Brain Differences Associated with the 16p11.2 Deletion. Notes: These diagrams represent transverse “cuts” across the brain on MRI scanning; the larger image at lower right is a composite sagittal view. The color-coding scale and + and – numbers show grey matter volumes in different anatomical regions, relative to a normal population. Some regions (blue) have reduced, and others (red and yellow) have increased grey matter volumes. One notable region with a reduced volume is the cingulate gyrus (the three images bracketed), evident as the blue coloring in the midline of the brain. Anomaly of the cingulate gyrus is associated with a number of neuropsychiatric phenotypes. Source: From C Modenato et al., Effects of eight neuropsychiatric copy number variants on human brain structure, Transl Psychiatry 11:399, 2021, with the permission of Springer Nature. Figure 25–5.  Deletion at Xp22.11 and Autism. Notes: These deletions encompass the gene DDX53, its position shown by the asterisk. DDX53 is otherwise known as an autism-related gene. The cases shown here are males with autism, identified in large cohorts: MSSNG, Simons Simplex Collection, and SPARK. These and other X-chromosomal CNVs (Mendes et al. 2025) are rare, but do cast light on the role of the X in autism. Source: From M Scala et al., Genetic variants in DDX53 contribute to autism spectrum disorder associated with the Xp22.11 locus, Am J Hum Genet 112:154–167, 2025. Courtesy SW Scherer, and with the permission of Elsevier.

780  PHENOTYPES It is uncommon for parents, having already had an autistic child, to come forward for CNV-focused prenatal diagnosis in a subsequent pregnancy. It is true that there is some ambivalence among students of allied health professions in this regard, which would likely be reflected in the wider public (Simonstein and Mashiach-Eizenberg 2016); and the counselor will be aware of the thinking behind a shift in descriptive language from “disorder” to “neurodiversity.” CANCER Rare examples are on record of a constitutional translocation disrupting or otherwise influencing a cancer-associated gene, or promoting mitotic malsegregation and thus comprising a “hit” in the cascade of events leading to the cellular phenotype of cancer over and above any reproductive risks to the balanced heterozygote. Tables 25–2, 25–3, and 25–4 set out cases from the literature. Notably, hematologic malignancy and renal cancer are overrepresented. The reader will note that some breakpoints are recurrent between different cancers. A well-recognized case is that of chromosome 3 translocations implicated in familial renal cancer, of which a number of examples have been published (Smith et al. 2020). According to one construction a three-hit sequence is envisaged, the first hit being the actual inheritance of the balanced translocation. Then, the mechanism is a mitotic malsegregation in an embryonal kidney cell. The derivative chromosome containing the 3p segment is lost (the second hit), and in consequence one daughter cell and thus the lineage from it has only one copy of distal 3p on the normal homolog. Thereafter, Figure 25–6.  Copy Number Variants in Autism. Notes: These data come from 12 cases within a whole cohort of 201 cases of autism, these 12 comprising 6% of the total. Causal variants included del 2p16.3, del 2q11.2 dn, del 2q37 dn, dup 16p11.2, dup 22q11.2, and t(21;22)(q22.13;12.1) dn. Dn, de novo; t, translocation. Source: From SM Musgrave et al., Genetic diagnostic outcomes from a 10-year research programme in autism in Aotearoa New Zealand. J Roy Soc New Zealand, 2024. Courtesy J Jacobsen. Chromosomal Phenotypes  781 on this remaining normal chromosome, a somatic mutation occurs in post-natal life at a tumor suppressor gene on 3p (such as VHL) in a kidney cell within this lineage (the third hit). Now the stage is set for a renal cancer to come into being. Certain germline copy-number variants may have an association with an increased cancer risk such as is proposed for the proximal del 16p11.2 BP4-BP5, associated with endometrial cancer (Stylianou et al. 2024). In familial breast cancer not due to one of the well-known Mendelian mutations, germline CNVs appear not to have a predisposing role (Walker et al. 2012). As for the role of germline CNVs in somatic cancer evolution (Raleigh et al. 2025), this is a matter well beyond the scope of this book. Otherwise, somatic cancer evolution is often built upon the phenomenon of multiple chromosome rearrangements, and this is the basis of the rare diagnosis of an occult malignancy in Table 25–2.  Translocations Associated with a Hematologic Cancer Risk TRANSLOCATION PROPOSED RELEVANT GENE TUMOR SYNDROME t(1;14)(p31;q21) Acute myeloid leukemia t(2;11)(q32;q23) Acute megakaryoblastic leukemia t(3;5)(p25;q22) Biphenotypic acute leukemia t(3;8)(p26;q21) Childhood myelodysplastic neoplasm t(7;22)(p13;q11.2) Hematological malignancy t(8;22)(q24.13;q11.21) TRC8 Chronic myeloid leukemia t(12;14)(p13.2;q23.1) ETV6 Acute lymphoblastic leukemia t(17;19)(q21;p13) MYO1F Myelodysplasia Notes: These translocations are apparently balanced, in the constitutional state, and not otherwise causing a phenotype. In some, the grounds for suspecting a causal link may be tenuous. Table 25–3.  Translocations Associated with a Renal Neoplasm Risk TRANSLOCATION PROPOSED RELEVANT GENE SYNDROME Many chr 3 rcp* VHL &c Von-Hippel Lindau, RCC t(2;17)(q21.1;q11.2) t(5;19)(p15.3;q12) UBE2QL1 RCC t(10;17)(q11.21;p11.2) FLCN RCC t(11;12)(p15.4;q15) NUP98 Renal angiomyolipomas t(11;22)(q23;q11)** RCC Notes: These translocations are apparently balanced in the constitutional state and not otherwise causing a phenotype. RCC = renal cell cancer. *Smith et al. (2020) review chromosome 3-associated RCC and suggest that most cases ascertained other than through a personal or family history appear to be associated with a very low risk of RCC. **This is the common recurrent t(11;22)(q23;q11) (p. 109). A previously proposed breast cancer risk with this translocation has since been discounted (Carter et al. 2010)

782  PHENOTYPES pregnant women having had a blood test for cfDNA as part of prenatal screening for aneuploidy, in whom the result turned out to be non-reportable (Turriff et al. 2024). CEREBRAL PALSY Cerebral palsy is an “umbrella term” that describes a disorder of motor function resulting from maldevelopment or injury to the developing brain. A genetic etiology is found in a sizeable minority, with considerable heterogeneity that overlaps with genetic causes of intellectual disability and epilepsy (Lewis et al. 2021). CNVs account for ~10% of unselected cases (Oskoui et al. 2015). DEVELOPMENTAL COORDINATION DISORDER This condition is also called dyspraxia, or the “clumsy child syndrome.” It is not uncommonly diagnosed in school-age children, quite often in coexistence with attention deficit disorder (Gibbs et al. 2007). In a relatively small Canadian cohort of such children the burden of CNV deletions or duplications in the 0.5 Mb–1.0 Mb range was significantly increased, and CNVs more often spanned brain-expressed genes compared with a control population (Mosca et al. 2016). Similarly, Cunningham et al. (2021) found that 91% Table 25–4.  Translocations Associated with Various Cancer Risks TRANSLOCATION PROPOSED RELEVANT GENE CANCER t(1:13)(q21:q12) WAVE3 Ganglioneuroblastoma t(1;17)(p36.2;q11.2) NBPF1, ACCN1 Neuroblastoma t(1;18)(p36.1;q21.1) SMAD4 Juvenile polyposis t(5;7)(q22;p15) APC Polyposis coli t(5;10)(q22;q25) APC Polyposis coli t(5;18)(q35.1;q21.2) Hodgkin lymphoma t(5;22)(q14.1;q11.23) SMARCB1 ATRT t(5;22)(q35.1;q11.2) NF2-associated medulloblastoma t(7;22)(p21;q11.2) Peripheral PNET t(8;22)(q24.13;q11.21) TRC8 Dysgerminoma t(14;20)(q24;p12) RAD51L1, BMP2 Thymoma t(16;22)(p13.3;q11.2) SMARCB1 ATRT t(16;22)(p13.3;q11.2q12) PNET Notes: These translocations are apparently balanced, in the constitutional state and not otherwise causing a phenotype. ATRT = atypical teratoid/rhabdoid tumor; PNET = primitive neuroectodermal tumor; NF2 = neurofibromatosis type 2; RCC = renal cell cancer. Sources: (Tables 25–2, 25–3, and 25–4) Aagaard et al. (2020), Betts et al. (2001), Blackburn et al. (2024), Bonne et al. (2007), Doyen et al. (2012), Gimelli et al. (2009), Hill et al. (2003), Järviaho et al. (2019), Kawamoto et al. (2017), Lovatel et al. (2023), Nicodème et al. (2005), Nunes et al. (2023), Panani et al. (2004), Panagopoulos et al. (2024), Poland et al. (2007), Ritter et al. (2015), Sahnane et al. (2016), Sawyer et al. (2003), Seo et al. (2015); Schoemaker et al. 2019; Smith et al. (2020), Sossey-Alaoui et al. (2002), Thibodeau et al. (2017), Vandepoele et al. (2008), Van der Luijt et al. (1995); Woodward et al. (2010).

Chromosomal Phenotypes  783 of children with neurodevelopmental CNVs screened positive for suspected developmental coordination disorder compared with 19% of controls. EPILEPSY Given the vulnerability of the brain to an incorrect genomic content, it is unsurprising that epilepsy is a frequent observation in many chromosomal disorders. Table 25–5 and Figure 25–7 show the classic chromosomal imbalances in which epilepsy is a particularly notable feature. A search for CNVs in children with epilepsy and neurodevelopmental delay may show a few with a pathogenic CNV, including del(16)p11.2 and del(1) p36 (Zhang et al. 2023b). A more detailed treatment of the particular case of epilepsy due to ring 20 appears in Chapter 11. GUT Malformations of the gastrointestinal system—notably duodenal atresia, jejunoileal atresia, and anorectal defects—have an association with certain chromosomal abnormalities. Meng and Jiang (2022) reviewed a series of prenatal diagnoses of a gut defect and showed a substantial increase in fetal chromosomal abnormality (34%) compared with the whole prenatally tested population (11%). Unsurprisingly, the rates were higher in those cases with concomitant other fetal malformation. Duodenal atresia is perhaps the classic example, being a well-recognized association with trisomy 21. Figure 25–8 shows a gut abnormality due to diaphragmatic hernia in trisomy 18, a defect reported in a number of different chromosomal abnormalities (Scott et al. 2022). As well as the classic trisomies, these segments were implicated in gastrointestinal defects in Meng and Jiang: 2p24, 3q, 4q24, and 10q26. A single case of a choledochal cyst in a child with dup 17q12 is reported in Kotalova et al. (2018); HNF1B is the likely relevant gene. Table 25–5.  Chromosomal Epilepsy Syndromes EPILEPSY SYNDROME CHROMOSOME Del 1p36 1p36 Wolf-Hirschhorn syndrome 4p Pallister Killian syndrome 12p Trisomy 12p 12p Ring 14 syndrome 14 Angelman syndrome 15q11q13 15q13.3 Microdeletion syndrome 15q13.3 InvDup (15) 15q11.2q13.1 Miller Dieker syndrome 17p13.3 18q– syndrome 18q22.1q23 Ring 20 syndrome 20 Down syndrome 21 Klinefelter syndrome X Figure 25–8.  Gut Defect in Trisomy 18. Notes: The appearance at autopsy of a baby with trisomy 18, who had died within an hour of birth, anterior view, from neck to upper abdomen. Loops of bowel, and part of the liver (L), have herniated up into the left hemi-thorax; the underlying defect was agenesis of the left dome of the diaphragm. A straw is placed in the defect. The heart (H) is secondarily displaced to the right. Figure 25–7.  Chromosomal Segments Associated with Epilepsy. Notes: This Miami plot analysis was based upon data of some thousands of individuals with seizure disorders and controls. Deletions are above, duplications below. Those particular CNVs meeting the threshold for accepting a probable cause (the chromosome imbalance) and effect (the epilepsy) relationship, namely, those crossing the orange lines, are identified as such. The chromosome 15 and 16 del/dups in particular, crossing far beyond the statistical threshold, stand out as incontrovertibly epilepsy-causing. The figures on the y axis represent a measure of probability. Source: From L Montanucci et al., Genome-wide identification and phenotypic characterization of seizure-associated copy number variations in 741,075 individuals, Nat Commun 14:4392, 2023. Courtesy C Leu and D Lal, and with the permission of Springer.

Chromosomal Phenotypes  785 HEARING LOSS Hearing loss of varying degree and type is a frequent concomitant of a chromosomal imbalance. Table 25–6 sets out the hearing phenotypes in some of the more common del/ dup syndromes. These CNVs are described in more detail in Chapter 14. HEART The process whereby the anatomical development of the heart and great vessels happens is complex indeed, and it is particularly vulnerable to a chromosomal imbalance (Figure 25–9). Almost every chromosome has been associated, when in imbalanced state, with a cardiac malformation. Three classic examples are Down syndrome, with ventricular Table 25–6.  Deletions and Duplications Associated with Hearing Loss Del/Dup HEARING LOSS CLASSIFICATION FREQUENCY OF HEARING LOSS CAUSATIVE GENE dup 5p13 occasional unkn del 7q11.23 SNHL, mild to moderate, progressive; specific phobias for certain sounds; hyperacusis >60% >90% (adults) ELN dup 7q11.23 ~5% ELN del/dup 7q21.3 SNHL, mixed hearing loss occasional unkn dup 8q12.2 Mondini malformation common CHD7 dup 9q21.11 Adult-onset, progressive loss occasional unkn del/dup 10p14 Early onset, moderate-to-severe SNHL common GATA3 dup 10q24 Conductive, or mixed due to chronic otitis media common unkn del/dup 11p15.5 Conductive hearing loss due to: fixation of the stapes (BWS); SNHL, cochlear malformation (RSS) rare unkn del 16p12.2p11.2 Frequent ear infections with conductive loss rare OTOA dup 16p12.2p11.2 Hyperacusis rare OTOA del 17p11.2 Usually mild and related to chronic otitis media common MYO15A dup 17p11.2 Mild high-frequency SNHL rare unkn del 22q11.2 SNHL and/or conductive loss; inner ear anomalies common TBX1 dup 22q11.2 Mostly conductive, due to recurrent otitis media common unkn Notes: SNHL = sensorineural hearing loss. Causative genes are known or at least hypothesized. unkn = unknown. BWS = Beckwith-Wiedemann, RSS = Russell-Silver syndrome. Source: Adapted from Tables in MT Bonati et al., Contiguous gene syndromes and hearing loss: A clinical report of Xq21 deletion and comprehensive literature review, Genes (Basel) 15:677, 2024.

786  PHENOTYPES septal defect; the dup 1q21.1 syndrome (p. 380); and the 22q11 deletion syndrome, with a wide range and particularly involving outflow defects (Table 25–7). Tan et al. (2022) document CNVs associated with congenital heart defects. KIDNEY We have listed various abnormalities of the kidney and urinary system seen in the three classic trisomy syndromes (Amor et al. 2003). Deletion or duplication of 17q12 has a particular association with renal malformation, with HNF1B the likely gene of concern (Luo et al. 2024; Molina et al. 2023). Familial transmission of del17q12 is on record, with Table 25–7.  The Range of Cardiovascular Defects in the 22q11.2 Deletion Syndrome DEFECT FREQ ASSOCIATED LESIONS RAA DAA ASCA BSVC LSVC MAPCA VSD Tetralogy of Fallot + pulmonary stenosis 19% + + + + + Tetralogy of Fallot + pulmonary atresia 22% + + + Interrupted aortic arch 4% + Ventricular septal defect 41% + + + + + + Atrial septal defect 15% + + + + + + Patent ductus arteriosus 11% + Aberrant subclavian artery 4% + No cardiovascular defect 26% Notes: These observations were made from a series of 27 cases. ASCA = aberrant subclavian artery; B/LSVC = bilateral/left superior vena cava; MAPCAs = major aortopulmonary collateral arteries; RAA = right-sided aortic arch; VSD = ventricular septal defect. Tetralogy of Fallot = VSD, overriding aorta, pulmonary stenosis, and right ventricular hypertrophy Source: CL Lee et al., 22q11.2 deletion syndrome in Taiwan: Clinical presentation and immune system status of patients, Int J Med Sci 20:1377–1385, 2023. Figure 25–9.  Heart Defects Associated with a Chromosomal Abnormality. Notes: From left to right in the images in the diagram above, the severity of the defect increases. Blue represents venous blood returning to the heart; red is oxygenated blood; purple is mixed, due to a septal defect. Arrows show flow of blood across the atrial and ventricular septal defects, in a “left-to-right shunt”. Source: From S Zaidi and M Brueckner, Genetics and genomics of congenital heart disease, Circ Res 120:923–940, 2017, with the permission of Wolters Kluwer.

Chromosomal Phenotypes  787 familial multicystic kidney disease (Aydın et al. 2022). Fetal hyperechogenic kidney is a sign that may be observed at prenatal ultrasonography; of the CNVs that may be identified in this setting, del17q12 is the most common (Huang et al. 2023b). OLIGOSPERMIA, AZOÖSPERMIA Oligospermia and azoöspermia (too few sperm, or none at all) is a frequent basis of male infertility. A chromosome abnormality is an occasional finding in the clinical work-up. A Robertsonian translocation is seen in 1½% to 3% of men presenting with oligospermia and a little under 1% of those with azoöspermia (Wiland et al. 2020). A reciprocal translocation is an infrequent finding (Chen and Zhou 2022). Klinefelter syndrome does not always present with the classic clinical picture, and it may take the recognition of infertility to arrive at that diagnosis. We refer elsewhere (p. 173) to the role of AZF deletions of the Y chromosome. RARE UNDIAGNOSED DISEASES To the practicing geneticist, rare diseases are common; one definition is a condition seen in fewer than 1 in 2,000 persons. A genomic study is often part of the investigative effort in such cases, and counselors will be familiar with the expression “diagnostic odyssey” (Kumar et al. 2023; Demidov et al. 2024). While Mendelian diagnoses are by far the most discovered in such broad-based genomic study, CNVs account for a notable minority (Figure 25–10). The categories of CNV thus identified are shown in Figure 25–11. Figure 25–10.  Discoveries at Genomic Diagnostic Odyssey. Notes: These data are based upon findings at the retrospective analysis, on exome sequencing, of 2,100 consecutive index cases referred for genome sequencing, mostly (71%) pediatric, with 29% adults. There were no specific inclusion or exclusion criteria. A genomic diagnosis, as shown in the graph, was reached in close to one-half. The large majority were Mendelian, autosomal dominant (AD), recessive (AR), and X-linked (XL) single nucleotide variants (SNVs) or molecular-level insertions and deletions (indels). Mitochondrial diagnoses (mt) were made in 3%. Copy number variants (CNVs), the focus of our present interest, accounted for 15%. Source: From F Guo et al., Evidence from 2100 index cases supports genome sequencing as a first-tier genetic test, Genet Med 26:100995, 2024. Courtesy M Hegde, and with the permission of Elsevier.

788  PHENOTYPES SCHIZOPHRENIA Chromosomal copy-number variants are the basis of a minority of schizophrenia, which is otherwise a largely polygenically determined condition. The three CNVs in which a causative effect is well accepted are del(15)p13.3, dup(16)p11.2, and del(22)q11.2 (Sullivan et al. 2024). The case in a number of others is less secure, but nevertheless it is likely several of these will come to be seen as established genetic contributors to a schizophrenic phenotype (Figure 25–12). There are variants that are rare but with strong effects (highly penetrant), and those that are common but of weak effect (low penetrance) (Rees and Kirov 2021). The most penetrant of the well-known CNVs is the del(22)q11.2 deletion, which is seen in 0.3% of those with schizophrenia versus 0.005% of control individuals: a sixty-fold difference. One in four del(22)q11 carriers develop the condition. Common polygenic risk factors may suffice to tip the genomic balance in these carriers such that schizophrenia evolves (Cleynen et al. 2021). A rare but apparently highly penetrant CNV is a 3.2 kb deletion at 10p15.2 (the locus of interest PITRM1) seen in a family in which schizophrenia is segregating practically as a dominant gene (Ormond et al. 2024). The practice of genetic counseling in the case of this common (~1% of the population) psychiatric disorder is evolving (Besterman 2024). Psychiatric genetic counselors “are trained to use a holistic approach to explain the interplay between genetic and environmental factors contributing to psychiatric disorders, and to address the emotional concerns and questions of the patients” (Austin 2020). Such counseling may “improve the understanding of disease recurrence risk, increase objective and subjective genetics knowledge, and reduce internalized stigma, worry, and self-blame, in individuals with schizophrenia and their families” (Costain et al. 2014). Schizophrenia due to a CNV will comprise only a small fraction of all cases, and counseling in such cases will need to be specifically tailored apropos (Morris et al. 2022). Figure 25–11.  CNVs Discovered in Agnostic Testing. Notes: These data reflect findings on 15,759 individuals from 6,633 families with undiagnosed rare disease. The CNV sizes vary (a) from <1 to >10 Mb, with most of 1-50 kb in size. The load of mendelian genes within CNVs is shown in (b), with most containing 2-24 genes. The considerable majority are assessed as being pathogenic (c). Source: From G Lemire et al., Exome copy number variant detection, analysis, and classification in a large cohort of families with undiagnosed rare genetic disease, Am J Hum Genet 111:863–876, 2024. Courtesy G Lemire and A O’Donnell-Luria, and with the permission of the American Society of Human Genetics.

Chromosomal Phenotypes  789 SKIN Pigmentary mosaicism, which may exist as an isolated observation or along with other manifestations, has a strong correlation with a chromosome abnormality (e.g., Figures 3–22 and 11–9). In a literature review of 263 karyotyped cases, Kromann et al. (2018) found 42% to be cytogenetically abnormal. Figure 25–13 shows the different seven archetypical patterns of hyperpigmentation that may be observed. These authors recommend that a cytogenetic analysis should be a routine test in such patients. A separate type of pigmentary condition is the café-au-lait macule, well-known from its association with neurofibromatosis type 1 but also an occasional observation in individuals carrying an autosomal ring chromosome (Sodré et al. 2010). SPEECH SOUND DISORDER A speech sound disorder (SSD) affects articulation or phonetic structure (due to poor motor abilities associated with the production of speech-sounds) and phonology (an Figure 25–12.  Deletions and Duplications Associated with Schizophrenia. Notes: The Manhattan plot shows dels and dups that are observed in large cohorts of cases of schizophrenia. Those reaching levels of statistical significance are shown extending above the blue line (moderately significant) and above the orange line (highly significant) (the y axis calibrates a measure of significance). Del 22q11.2 and dup 16p11.2 are obvious stand-outs. Source: From CR Marshall et al., Contribution of copy number variants to schizophrenia from a genome-wide study of 41,321 subjects, Nat Genet 49:27–35, 2016. Courtesy J Sebat, and with the permission of Springer Nature.

790  PHENOTYPES inability to apply linguistic rules to combine sounds to form words). In simple terms, it is an inability to put words together. It can be a component of autism, hearing impairment, or intellectual disability, but here we consider it as the predominant trait. In its more severe form, it is referred to as childhood apraxia of speech (CAS). A genetic basis is common, and a number of loci are implicated (Morgan et al. 2024). We refer (Chapter 14) to deletions at 7q31, 12p13.33, and proximal 16p11.2 as being causative in cases with a broader neurofunctional phenotype. Chan et al. (2024) identify a number of other SSD-associated CNVs, including in particular deletions at 2q24.3, 6p12.3p12.2, and 11q23.2q23.3, in their study of families in which a proband had CAS, and other family members had a less severe SSD. Most cases were inherited; a few had arisen de novo. SUDDEN INFANT DEATH Brownstein et al. (2022) undertook CNV analysis in a large series of Sudden Unexplained Death in the Pediatric Age Group, ages at death from 1.5 months to 28 months; in five out of the 116 cases (4%) a presumed pathogenic deletion was identified (Table 25–8). Figure 25–13.  Patterns of Pigmentary Mosaicism. Notes: Kromann et al. distinguish types a through h, as follows: (a) type 1a, (b) type 1b, (c) type 2, (d) type 3, (e) type 4, (f ) type 5, (g) type 6 seen from the front, (h) type 6 seen from the back Source: From AB Kromann et al., Pigmentary mosaicism: a review of original literature and recommendations for future handling, Orphanet J Rare Dis 13:39, 2018. Courtesy A Bygum, and with the permission of Springer Nature. Chromosomal Phenotypes  791 Additionally, a further nine cases had a deletion or a duplication that was assessed as being likely pathogenic, for a total 12% with a known or probably causative CNV. Brownstein and colleagues make the case for a chromosome study, along with exome sequencing, as a routine test in such cases. Table 25–8.  Deletions and Duplications Seen in Sudden Unexplained Childhood Death. SEGMENT del/dup SIZE 2p16.3* del 108 kb 2p21 dup 2.8 kb 2p23.1 dup 174 kb 4q31.22 * del 348 kb 5q13.2 * del 1.8 Mb 7q36.3 dup 226 kb 8p23.2 del 223 kb 13q32.3 dup 117 kb 13q34 dup 140 kb 15q11.2 (×2) del 245-246 kb 15q15.3 * del 98 kb 22q11.21 dup 13.4 kb 22q13.33 dup 275 kb Xp22.33 * del 800 kb Note: Sudden Unexplained Death in the Pediatric Age Group encompasses Sudden Infant Death Syndrome (under 1 year; “cot death”) and Sudden Unexplained Death in Childhood (over 1 year). These cases came from a cohort of 116 Cases. In the five asterisked cases, the del was presumed to have been pathogenic; in the remainder, pathogenicity was considered likely. The dup2p21 and dup 22q11.21 were seen in the same child. In an earlier such study, a del6p22, dup8q24.3, and del22q13.3 had been documented (Toruner et al. 2009). Source: CA Brownstein et al., Copy number variation and structural genomic findings in 116 cases of sudden unexplained death between 1 and 28 months of age, Adv Genet (Hoboken) 4:2200012, 2022.