Statement on guidance for genetic counseling in advanced paternal age.

In 1996, a practice guideline on genetic counseling for advanced paternal age was published. The current document updates the state of knowledge of advanced paternal age effects on single gene mutations, chromosome anomalies, and complex traits.

There is no clearly accepted definition of advanced paternal age. A frequently used criterion is any man aged 40 years or older at the time of conception. The current population mean paternal age is 27 years.

Advanced paternal age is associated with an increased risk of new gene mutations. Because of the large number of cell divisions during spermatogenesis, the mutation rate for base substitutions is much higher in men than women, and increases with paternal age. The risk for genetic defects increases linearly for some conditions, and exponentially for others.1–3 The conditions most strongly associated with advanced paternal age are those caused by mutations in the form of single base substitutions in the FGFR2, FGFR3, and RET genes, and include Pfeiffer syndrome, Crouzon syndrome, Apert syndrome, achondroplasia, thanatophoric dysplasia, as well as MEN2A and MEN2B.4 Some dominant conditions that are caused by gene changes that include both point mutations and base pair deletions (e.g., neurofibromatosis) show a lesser association with paternal age. Other dominant conditions show no association with increased paternal age.5 Although Friedman6 had estimated that the risk for autosomal dominant disorders affecting offspring of fathers aged 40 or more was 0.3–0.5%, it is now thought that the actual risk is lower.7 There is also a growing body of evidence that advanced paternal age is associated with an increased risk for complex disorders such as some congenital anomalies, schizophrenia, autism spectrum disorders, and some forms of cancer.8 –12 For most conditions the relative risk is two or less. However, the mechanism for the increased risk is unknown, and in some cases, the observed paternal age effect may be an artifact of some other causative factor.

In general, for autosomes and sex chromosomes, there is no compelling evidence that chromosomal aberrations (aneuploidy or structural chromosome abnormalities) are significantly increased in newborns as paternal age increases. The low incidence of paternally derived extra chromosomes in trisomies combined with the relatively small number of children fathered by older men makes it difficult to demonstrate a paternal age effect. Two possible exceptions are trisomy 21 and Klinefelter syndrome. Recent data on Down syndrome suggest a paternal age effect, either acting alone or in combination with a maternal age effect.13,14 This observation is supported by reports of increased aneuploidy rates in sperm for some of the chromosomes, including 21 and the sex chromosomes.15–17 In summary, there is a wide range of genetic disorders that may be related to advanced paternal age (Table 1). Overall, it seems that the risk of birth defects and some chromosome disorders may be minimally increased, and the risk for later onset disorders may also show a small increase with advanced paternal age. There are currently no screening or diagnostic test panels which specifically target those conditions that increase with paternal age. If the older male’s partner is currently pregnant, the pregnancy should be treated as any other according to prenatal diagnosis guidelines established by the American College of Medical Genetics and American College of Obstetricians and Gynecologists,18–20 with the prenatal counseling session including a discussion about the potentially increased risk of Down syndrome attributable to increased paternal age. Because of this and the possibility of ultrasound detection of some of the features of the autosomal dominant conditions noted above (e.g., thanatophoric dysplasia), an ultrasound is recommended at 18–20-weeks gestation to evaluate fetal growth and development. However, it is unlikely to detect many of the conditions of interest. Prospective couples should receive individualized genetic counseling to address specific concerns.

Table 1

Paternal age risks

Type	Specific condition	Age (relative to reference age)	Relative risk (CI, if available)	Population risk (or reference risk)	Adjusted risk	References (first author’s name only)
Autosomal dominant	Achondroplasia	>50 (25–29)	7.8	1/15,000	1/1923	Risch1
		30–34 (<20)	3.5		1/4285	Tiemann-Boege21
		35–39 (<20)	4		1/3750
		40–44 (<20)	8		1/1875
		45–49 (<20)	9		1/1666
		50–54 (<20)	12		1/1250
	Apert	>50 (25–29)	9.5	1/50,000	1/5263	Risch1
	Pfeiffer	>50 (25–29)	6	1/100,000	1/16,666	Glaser22
	Crouzon	>50 (25–29)	8	1/50,000	1/6250
	Progeria	Unknown	Effect seen	“Exceedingly rare”
	MEN2A	Unknown	Effect seen	1/30,000
	MEN2B	Unknown	Effect seen	1/30,000
	Neurofibromatosis I	>50 (25–29)	3.7a	1/3000–1/4000	1/810–1/1080	Risch1
		>40 (<30)	2.9		1/1034–1/1380	Bunin23
	Osteogenesis imperfecta	>35 (<25)	2.5	1/10,000	1/4000	Carothers24
		>35 (<35)	1.37 (0.73–6.89)		1/7300	Orioli25
	Thanatophoric dysplasia	>35 (<35)	3.18 (1.48–6.89)	1/20,000–1/50,000	1/6290–1/15,723	Orioli25
	Retinoblastoma	>45	3a (0.21–41.7)	1/15,000–1/20,000	1/5000–1/6667	Dockerty, Yip26,27
		>35 (<35)	1.34 (1.04–1.74)		1/11,200–1/14,925	Moll28
		>50 (32.5)	5		1/3000–1/4000	DerKinderen29
Chromosomal	Down syndrome	40–44 (20–29)	1.37 (0.48–3.86)	1/1200 (mat. age 20–29)	1/876	Zhu30
		45–49 (20–29)	2.68 (0.76–9.51)		1/448
		>49 (20–29)	4.5 (1.0–20.3)		1/267
		40–44 (25–29)	1.45 (1.26–1.68)	Use maternal age as baseline for counseling purposesb		Yang31
		45–49 (25–29)	1.28 (1.04–1.57)
		>49 (25–29)	1.39 (1.04–1.83)
		None given	“May be increased”			Kuhnert16
		None given	“Paternal age effect in association with maternal age (>35) effect”			Fisch14
	Klinefelter syndrome	>50 (20’s)	1.6c (0.69–3.0)	1/500 men	1/312 men	Lowe32
Congenital anomalies	VSD	>40 (<40)	1.69a	1/200	1/118	Olshan33
	ASD	>35	1.95a	1/400	1/205	Lian11
	Tracheoesophageal fistula	>50 (25–29)	2.55 (1.28–4.6)	1/3600	1/1412	Yang31
Other complex disorders	Childhood leukemia	>35	1.5	1/25,000	1/16,667	Murray34
		>40 (<25)	1.14 (0.85–1.53)		1/21930	Yip27
	Childhood CNS tumor	30–34 (<25)	1.34 (1.04–1.72)	1/36,000	1/26,866	Yip27
		35–39 (<25)	1.4 (1.04–1.86)		1/25,714
		>40 (<25)	1.69 (1.21–2.35)		1/21,302
	Childhood type 1 diabetes	>34 (<25)	1.52 (1.1–2.09)	1/415	1/273	Cardwell35
	Epilepsy	35–39	1.18 (1.02–1.26)	1/100	1/85	Vestergaard36
		40–45	1.3 (1.08–1.55)		1/770
	Schizophrenia	>50 (20–24)	4.62 (2.28–9.36)	1/100	1/22	Rasmussen37
		35–44 (15–24)	1.6 (1.0–2.6)		1/62.5	Zammit38
		45–54 (15–24)	1.6 (0.8–3.1)		1/62.5
		>54 (15–24)	3.8 (1.3–11.8)		1/26
		>49 (<25)	3		1/33	Malaspina12
		>32 (<28)	3 (1.49–6.04)		1/33	Tsuchiya39
	Autism	>40 (<30)	5.75 (2.65–12.46)	1/1000	1/174	Reichenberg40
		Unknown	Effect seen			Cantor9
	Autism spectrum disorders	35–39 (25–29)	1.38 (1.04–1.84)	1/200	1/145	Croen41
		>39 (25–29)	1.52 (1.1–2.1)		1/131
	Breast cancer	>40 (<30)	1.6 (1.04–2.32)	1/8.5	1/5.3	Choi42
	Prostate cancer	>38 (<27)	1.7 (1.0–2.8)	1/5.9	1/3.5	Zhang43
	Multiple sclerosis	51–55 (21–25)	2.0 (1.35–2.96)			Montgomery44
Other	Spontaneous miscarriages	>35 (<35)	1.26 (1.0–1.6)	1/7	1/5.3	Slama45
		>39 (25–29)	1.6 (1.2–2.0)		1/4	Kleinhaus46
	Relative infertility	>39 (<39)	2.3 (1.67–3.17)	1/14 couples	1/6.2	De la Rochebrochard47
	Low birth weight	>34 (20–34)	1.7 (1.3–2.2)	1/40	1/23	Reichman48
	Preeclampsia	35–44 (25–34)	1.24 (1.05–1.46)	1/62	1/50	Harlap49
		>44 (25–34)	1.8 (1.04–1.51)	1/62	1/34
Total risk	For 86 examined congenital anomalies	>40 (<20)	1.2	1/50	1/42	Lian11
		>50 (<20)	1.3		1/38

This table is meant to show the findings of various studies examining the effect of paternal age on the condition in question. It is not meant to be a comprehensive guide to counseling, but to merely indicate conditions which have been studied and results obtained from those studies.

Increased risk not shown by other studies.

Suggestion for this adjustment made by the author of this document. There are no data regarding use of paternal age for counseling for serum screening results.

Based on frequency of XY sperm.